Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior
Abstract:Rapidly activating and inactivating A-type K+ currents (IA) encoded by Kv4.2 and Kv4.3 pore-forming (α) subunits of the Kv4 subfamily are key regulators of neuronal excitability. Previous studies have suggested a role for Kv4.1 α-subunits in regulating the firing properties of mouse suprachiasmatic nucleus (SCN) neurons. To test this, we utilized an RNA-interference strategy to knockdown Kv4.1, acutely and selectively, in the SCN. Current-clamp recordings revealed that the in vivo knockdown of Kv4.1 significan… Show more
“…Its knock‐down had a greater effect at night (Hermanstyne et al . ), with similar effects reported in Drosophila (Feng et al . ).…”
Section: Discussionsupporting
confidence: 88%
“…; Hermanstyne et al . ). On the other hand, Shaw regulates the firing rate in a range of Drosophila neurons including clock neurons probably by a separate mechanism to Shal, via controlling the resting membrane potential (Tsunoda & Salkoff, ; Hodge et al .…”
Section: Discussionmentioning
confidence: 97%
“…; Hermanstyne et al . ). Kv4.2 (Shal) and Kv1.4 (Shaker) are expressed in the SCN and loss of function mutants disrupt the clock neuron neuronal firing, circadian behaviour and circadian period of PER2 expression, reiterating the importance and interdependence of the rhythmic changes in membrane excitability of clock neurons and the molecular clock (Granados‐Fuentes et al .…”
Section: Introductionmentioning
confidence: 97%
“…, ; Hermanstyne et al . ). Additionally, block of Shal function by a dominant negative (DN) transgene in Drosophila has been associated with clock neuronal hyperexcitation, preferentially increasing clock neuron firing rates around ZT13 when rhythmic change in resting membrane potential and firing rate are low, disrupting PDF signalling to DN1 clock neurons (Feng et al .…”
Section: Introductionmentioning
confidence: 97%
“…Shal/Kv4 is an A-type channel regulating neuronal firing (Gasque et al 2005), including SCN firing rates, and affects circadian rhythms with knock-down having greater effect at night (Itri et al 2010;Hermanstyne et al 2017). Kv4.2 (Shal) and Kv1.4 (Shaker) are expressed in the SCN and loss of function mutants disrupt the clock neuron neuronal firing, circadian behaviour and circadian period of PER2 expression, reiterating the importance and interdependence of the rhythmic changes in membrane excitability of clock neurons and the molecular clock (Granados-Fuentes et al 2012Hermanstyne et al 2017). Additionally, block of Shal function by a dominant negative (DN) transgene in Drosophila has been associated with clock neuronal hyperexcitation, preferentially increasing clock neuron firing rates around ZT13 when rhythmic change in resting membrane potential and firing rate are low, disrupting PDF signalling to DN1 clock neurons (Feng et al 2018).…”
As in mammals, Drosophila circadian clock neurons display rhythms of activity with higher action potential firing rates and more positive resting membrane potentials during the day. This rhythmic excitability has been widely observed but, critically, its regulation remains unresolved. We have characterized and modelled the changes underlying these electrical activity rhythms in the lateral ventral clock neurons (LNvs). We show that currents mediated by the voltage‐gated potassium channels Shaw (Kv3) and Shal (Kv4) oscillate in a circadian manner. Disruption of these channels, by expression of dominant negative (DN) subunits, leads to changes in circadian locomotor activity and shortens lifespan. LNv whole‐cell recordings then show that changes in Shaw and Shal currents drive changes in action potential firing rate and that these rhythms are abolished when the circadian molecular clock is stopped. A whole‐cell biophysical model using Hodgkin‐Huxley equations can recapitulate these changes in electrical activity. Based on this model and by using dynamic clamp to manipulate clock neurons directly, we can rescue the pharmacological block of Shaw and Shal, restore the firing rhythm, and thus demonstrate the critical importance of Shaw and Shal. Together, these findings point to a key role for Shaw and Shal in controlling circadian firing of clock neurons and show that changes in clock neuron currents can account for this. Moreover, with dynamic clamp we can switch the LNvs between morning‐like and evening‐like states of electrical activity. We conclude that changes in Shaw and Shal underlie the daily oscillation in LNv firing rate.
“…Its knock‐down had a greater effect at night (Hermanstyne et al . ), with similar effects reported in Drosophila (Feng et al . ).…”
Section: Discussionsupporting
confidence: 88%
“…; Hermanstyne et al . ). On the other hand, Shaw regulates the firing rate in a range of Drosophila neurons including clock neurons probably by a separate mechanism to Shal, via controlling the resting membrane potential (Tsunoda & Salkoff, ; Hodge et al .…”
Section: Discussionmentioning
confidence: 97%
“…; Hermanstyne et al . ). Kv4.2 (Shal) and Kv1.4 (Shaker) are expressed in the SCN and loss of function mutants disrupt the clock neuron neuronal firing, circadian behaviour and circadian period of PER2 expression, reiterating the importance and interdependence of the rhythmic changes in membrane excitability of clock neurons and the molecular clock (Granados‐Fuentes et al .…”
Section: Introductionmentioning
confidence: 97%
“…, ; Hermanstyne et al . ). Additionally, block of Shal function by a dominant negative (DN) transgene in Drosophila has been associated with clock neuronal hyperexcitation, preferentially increasing clock neuron firing rates around ZT13 when rhythmic change in resting membrane potential and firing rate are low, disrupting PDF signalling to DN1 clock neurons (Feng et al .…”
Section: Introductionmentioning
confidence: 97%
“…Shal/Kv4 is an A-type channel regulating neuronal firing (Gasque et al 2005), including SCN firing rates, and affects circadian rhythms with knock-down having greater effect at night (Itri et al 2010;Hermanstyne et al 2017). Kv4.2 (Shal) and Kv1.4 (Shaker) are expressed in the SCN and loss of function mutants disrupt the clock neuron neuronal firing, circadian behaviour and circadian period of PER2 expression, reiterating the importance and interdependence of the rhythmic changes in membrane excitability of clock neurons and the molecular clock (Granados-Fuentes et al 2012Hermanstyne et al 2017). Additionally, block of Shal function by a dominant negative (DN) transgene in Drosophila has been associated with clock neuronal hyperexcitation, preferentially increasing clock neuron firing rates around ZT13 when rhythmic change in resting membrane potential and firing rate are low, disrupting PDF signalling to DN1 clock neurons (Feng et al 2018).…”
As in mammals, Drosophila circadian clock neurons display rhythms of activity with higher action potential firing rates and more positive resting membrane potentials during the day. This rhythmic excitability has been widely observed but, critically, its regulation remains unresolved. We have characterized and modelled the changes underlying these electrical activity rhythms in the lateral ventral clock neurons (LNvs). We show that currents mediated by the voltage‐gated potassium channels Shaw (Kv3) and Shal (Kv4) oscillate in a circadian manner. Disruption of these channels, by expression of dominant negative (DN) subunits, leads to changes in circadian locomotor activity and shortens lifespan. LNv whole‐cell recordings then show that changes in Shaw and Shal currents drive changes in action potential firing rate and that these rhythms are abolished when the circadian molecular clock is stopped. A whole‐cell biophysical model using Hodgkin‐Huxley equations can recapitulate these changes in electrical activity. Based on this model and by using dynamic clamp to manipulate clock neurons directly, we can rescue the pharmacological block of Shaw and Shal, restore the firing rhythm, and thus demonstrate the critical importance of Shaw and Shal. Together, these findings point to a key role for Shaw and Shal in controlling circadian firing of clock neurons and show that changes in clock neuron currents can account for this. Moreover, with dynamic clamp we can switch the LNvs between morning‐like and evening‐like states of electrical activity. We conclude that changes in Shaw and Shal underlie the daily oscillation in LNv firing rate.
Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, are not well established. The BACHD mouse model of HD exhibits disrupted behavioral and physiological rhythms, including decreased electrical activity in the central circadian clock (suprachiasmatic nucleus, SCN). In this study, electrophysiological techniques were used to explore the ionic underpinning of the reduced spontaneous neural activity in male mice. We found that SCN neural activity rhythms were lost early in the disease progression and was accompanied by loss of the normal daily variation in resting membrane potential in the mutant SCN neurons. The low neural activity could be transiently reversed by direct current injection or application of exogenous N-methyl-d-aspartate (NMDA) thus demonstrating that the neurons have the capacity to discharge at WT levels. Exploring the potassium currents known to regulate the electrical activity of SCN neurons, our most striking finding was that these cells in the mutants exhibited an enhancement in the large-conductance calcium activated K (BK) currents. The expression of the pore forming subunit (Kcnma1) of the BK channel was higher in the mutant SCN. We found a similar decrease in daytime electrical activity and enhancement in the magnitude of the BK currents early in disease in another HD mouse model (Q175). These findings suggest that SCN neurons of both HD models exhibit early pathophysiology and that dysregulation of BK current may be responsible.
Transient outward potassium currents were first described nearly 60 years ago, since then major strides have been made in understanding their molecular basis and physiological roles. From the large family of voltage-gated potassium channels members of 3 subfamilies can produce such fast-inactivating A-type potassium currents. Each subfamily gives rise to currents with distinct biophysical properties and pharmacological profiles and a simple workflow is provided to aid the identification of channels mediating A-type currents in native cells. Their unique properties and regulation enable A-type K + channels to perform varied roles in excitable cells including repolarisation of the cardiac action potential, controlling spike and synaptic timing, regulating dendritic integration and long-term potentiation as well as being a locus of neural plasticity.
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