The facilitating effect of systemic administration of Kv7/M channel blocker XE991 on LTP induction in the hippocampal CA1 area independent of muscarinic activation

doi:10.1016/j.neulet.2009.05.042

Neuroscience Letters

Volume 461, Issue 1, 8 September 2009, Pages 25-29

https://doi.org/10.1016/j.neulet.2009.05.042 Get rights and content

Abstract

A large amount of in vitro studies demonstrate suppression of M-current in hippocampal neurons by Kv7/M channel blocker results in depolarization of membrane potential and release of neurotransmitters, such as acetylcholine and glutamate, suggesting that Kv7/M channel may play important roles in regulating synaptic plasticity. In the present study, we examined the in vivo effect of Kv7/M channel inhibition on the long-term potentiation (LTP) induction at basal dendrites in hippocampal CA1 area of urethane-anaesthetized rats. The Kv7/M channel was inhibited by intraperitoneal injection of XE991 (10 mg/kg) and the LTP of field excitatory postsynaptic potential (fEPSP) was induced by supra-threshold high frequency stimulation (S1 HFS). A weak protocol which was just below the threshold for evoking LTP was used as sub-threshold high frequency stimulation (S2 HFS). XE991 did not significantly alter the slope of fEPSP and the magnitude of LTP induced by S1 HFS, suggesting that Kv7/M channel inhibition had little or no effect on glutamatergic transmission under basal conditions. However, XE991 could make S2 HFS evoke LTP even after the application of the muscarinic cholinergic (mACh) receptor antagonist scopolamine, suggesting that Kv7/M channel inhibition lowered the threshold for LTP induction and the effect was independent of muscarinic activation. Based on the above findings, we concluded that the facilitating effect of XE991 on LTP induction is not mediated by its ability to enhance the release of acetylcholine; therefore, Kv7/M channel blockers may provide a therapeutic benefit to cholinergic deficiency-related cognitive impairment, e.g., Alzheimer's disease.

Section snippets

Acknowledgements

This study was supported by grants from the Science Foundation for Young Scholars of Shanghai Municipal Health Bureau (2008Y021), the Research Foundation for Young Teachers of Shanghai Jiao Tong University School of Medicine (2008), the Shanghai Education Committee (ZDXK2001) and the Specialized Research Foundation for Outstanding Young Teachers of Shanghai Education Committee (2005). The authors thank Dr. Guo-yuan Hu and Xiao-ling Hu for their helpful suggestions of this experiment.

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Impaired channel activity of KCNQ4 is associated with nonsyndromic autosomal dominant hearing loss (DFNA2) and hearing impairment owing to the role of KCNQ4 in cochlear hair cells (Xia et al., 2020; Kharkovets et al., 2000; Jung et al., 2019). Selective neuronal KCNQ openers can be used for the treatment of epilepsy and neurodevelopmental disorders, while KCNQ blockers may be developed as cognitive enhancers to treat neurodegenerative disorders (Barrese et al., 2018; Zheng et al., 2013; Song et al., 2009; Gribkoff, 2008). Therefore, structural information about these channels in complex with their endogenous and candidate therapeutic ligands is of high interest in guiding future basic, translational, and clinical work.
The KCNQ family (KCNQ1–KCNQ5) of voltage-gated potassium channels plays critical roles in many physiological and pathological processes. It is known that the channel opening of all KCNQs relies on the signaling lipid molecule phosphatidylinositol 4,5-bisphosphate (PIP2). However, the molecular mechanism of PIP2 in modulating the opening of the four neuronal KCNQ channels (KCNQ2–KCNQ5), which are essential for regulating neuronal excitability, remains largely elusive. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 determined in complex with the activator ML213 in the absence or presence of PIP2. Two PIP2 molecules are identified in the open-state structure of KCNQ4, which act as a bridge to couple the voltage-sensing domain (VSD) and pore domain (PD) of KCNQ4 leading to the channel opening. Our findings reveal the binding sites and activation mechanisms of ML213 and PIP2 for neuronal KCNQ channels, providing a framework for therapeutic intervention targeting on these important channels.
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This is an example of hyperpolarizing currents contributing to the expression of LTP, by keeping the synapse net excitability under control in order to avoid an overstimulation. Several studies highlighted the positive effect that muscarinic activation have facilitating the induction of LTP in the hippocampus (Song et al., 2009; Buchanan et al., 2010; Fontan-Lozano et al., 2011; Petrovic et al., 2012) and other brain areas (Peng et al., 2017), presumably by inducing an enhancement of glutamate release (Sun and Kapur, 2012). In particular, it seems that LTP in the CA1 neurons of the hippocampus can be reinforced when this is induced with a parallel stimulation in the stratum oriens, which triggers the release of endogenous acetylcholine from cholinergic terminals.
Besides their primary function mediating the repolarization phase of action potentials, potassium channels exquisitely and ubiquitously regulate the resting membrane potential of neurons and therefore have a key role establishing their intrinsic excitability. This group of proteins is composed of a very diverse collection of voltage-dependent and -independent ion channels, whose specific distribution is finely tuned at the level of the synapse. Both at the presynaptic and postsynaptic membranes, different types of potassium channels are subjected to modulation by second messenger signaling cascades triggered by metabotropic receptors, which in this way serve as a link between neurotransmitter actions and changes in the neuron membrane excitability. On the one hand, by regulating the resting membrane potential of the postsynaptic membrane, potassium channels appear to be critical towards setting the threshold for the induction of long-term potentiation and depression. On the other hand, these channels maintain the presynaptic membrane potential under control, therefore influencing the probability of neurotransmitter release underlying different forms of short-term plasticity. In the present review, we examine in detail the role of metabotropic receptors translating their activation by different neurotransmitters into a final effect modulating several types of potassium channels. Furthermore, we evaluate the consequences that this interplay has on the induction and maintenance of different forms of synaptic plasticity.
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Facilitation of LTP contains both the downregulation of LTP threshold and the enhancement of LTP magnitude. And when subthreshold stimulation induces LTP successfully, the magnitude of LTP induced by suprathreshold stimulation can be increased (Lalo et al., 2016; Suo et al., 2017; Zhang et al., 2012), decreased (Ding et al., 2015; Lalo et al., 2016) or unchanged (Lu et al., 1999; Pyapali et al., 1998; Song et al., 2009). Therefore, we further detected whether the magnitude of 300 ng BDNF-induced spinal LTP was changed in nIN-IN rats.
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However, some previous studies have demonstrated that pharmacological inhibition of KCNQ/Kv7 channels facilitates the memory process and hippocampal LTP. In their studies, XE-991 facilitates the object recognition memory (Fontan-Lozano et al., 2011) and LTP induced by sub-threshold stimulation which provoke short-term changes in synaptic efficacy (Song et al., 2009; Fontan-Lozano et al., 2011). They pointed out that XE-991 lowered the threshold for LTP induction and did not alter LTP induced by supra-threshold stimulation.
Spatial memory retrieval and hippocampal long-term potentiation (LTP) are impaired by stress. KCNQ/Kv7 channels are closely associated with memory and the KCNQ/Kv7 channel activator flupirtine represents neuroprotective effects. This study aims to test whether KCNQ/Kv7 channel activation prevents acute stress-induced impairments of spatial memory retrieval and hippocampal LTP. Rats were placed on an elevated platform in the middle of a bright room for 30 min to evoke acute stress. The expression of KCNQ/Kv7 subunits was analyzed at 1, 3 and 12 h after stress by Western blotting. Spatial memory was examined by the Morris water maze (MWM) and the field excitatory postsynaptic potential (fEPSP) in the hippocampal CA1 area was recorded in vivo. Acute stress transiently decreased the expression of KCNQ2 and KCNQ3 in the hippocampus. Acute stress impaired the spatial memory retrieval and hippocampal LTP, the KCNQ/Kv7 channel activator flupirtine prevented the impairments, and the protective effects of flupirtine were blocked by XE-991 (10,10-bis(4-Pyridinylmethyl)-9(10H)-anthracenone), a selective KCNQ channel blocker. Furthermore, acute stress decreased the phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9 in the hippocampus, and flupirtine inhibited the reduction. These results suggest that the KCNQ/Kv7 channels may be a potential target for protecting both hippocampal synaptic plasticity and spatial memory retrieval from acute stress influences.
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The facilitating effect of systemic administration of Kv7/M channel blocker XE991 on LTP induction in the hippocampal CA1 area independent of muscarinic activation

Abstract

Section snippets

Acknowledgements

Adv. Pharmacol.

Pharmacol. Biochem. Behav.

Neurosci. Lett.

Curr. Opin. Neurobiol.

J. Biol. Chem.

Neurosci. Lett.

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone

Nature

Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3C-terminal domains

Proc. Natl. Acad. Sci. U.S.A.

Cognition enhancement by the acetylcholine releaser DuP 996

Drug Dev. Res.

Colocalization and coassembly of two human brain. M-type potassium channel subunits that are mutated in epilepsy

Proc. Natl. Acad. Sci. U.S.A.

M channel KCNQ2 subunits are localized to key sites for control of neuronal network oscillations and synchronization in mouse brain

J. Neurosci.

Asynchronous pre- and postsynaptic activity induces associative long-term depression in area CA1 of the rat hippocampus in vitro

Proc. Natl. Acad. Sci. U.S.A.

KCNQ2 is a nodal K+ channel

J. Neurosci.

2-Fluoro-4-pyridinylmethyl analogues of linopirdine as orally active acetylcholine release-enhancing agents with good efficacy and duration of action

J. Med. Chem.

Cognition enhancement strategies by ion channel modulation of neurotransmission

Curr. Pharm. Des.

The cholinergic pathology in Alzheimer's disease—discrepancies between clinical experience and pathophysiological findings

J. Neural Transm.

Kv7/KCNQ/M and HCN/h, but not KCa2/SK channels, contribute to the somatic medium after-hyperpolarization and excitability control in CA1 hippocampal pyramidal cells

J. Physiol.

Muscarinic suppression of a novel voltage-sensitive K⁺ current in a vertebrate neurone

KCNQ2 is a nodal K⁺ channel