Rapid activity-dependent modulation of the intrinsic excitability through up-regulation of KCNQ/Kv7 channel function in neonatal spinal motoneurons

Abstract

Activity-dependent changes in the properties of the motor system underlie the necessary adjustments in its responsiveness on the basis of the environmental and developmental demands of the organism. Although plastic changes in the properties of the spinal cord have historically been neglected because of the archaic belief that the spinal cord is constituted by a hardwired network that simply relays information to muscles, plenty of evidence has been accumulated showing that synapses impinging on spinal motoneurons undergo short- and long-term plasticity. In the brain, brief changes in the activity level of the network have been shown to be paralleled by changes in the intrinsic excitability of the neurons and are suggested to either reinforce or stabilize the changes at the synaptic level. However, rapid activity-dependent changes in the intrinsic properties of spinal motoneurons have never been reported. In this study, we show that in neonatal mice the intrinsic excitability of spinal motoneurons is depressed after relatively brief but sustained changes in the spinal cord network activity. Using electrophysiological techniques together with specific pharmacological blockers of KCNQ/Kv7 channels, we demonstrate their involvement in the reduction of the intrinsic excitability of spinal motoneurons. This action results from an increased M-current, the product of the activation of KCNQ/Kv7 channels, which leads to a hyperpolarization of the resting membrane potential and a decrease in the input resistance of spinal motoneurons. Computer simulations showed that specific up-regulations in KCNQ/Kv7 channels functions lead to a modulation of the intrinsic excitability of spinal motoneurons as observed experimentally. These results indicate that KCNQ/Kv7 channels play a fundamental role in the activity-dependent modulation of the excitability of spinal motoneurons.

Long‐lasting modifications of motoneuron firing properties by trans‐spinal direct current stimulation in rats

“…The observed changes could also arise from alterations in motoneuron passive membrane properties, such as input resistance; however, these values were not modified by any type of polarization during any of the analysed recording periods. Another possibility is that alterations may occur in the activity levels of several types of ion channels that are responsible for the initiation of ionic currents, such as the M‐current or the Ih current, which might modify the motoneuron f‐I relationship and firing properties (Biel, Wahl‐Schott, Michalakis, & Zong, ; Lombardo, Sun, & Harrington, ) or the channels responsible for the activation of potassium conductance or the inactivation of sodium conductance (Catterall, ). However, in our previous paper (Bączyk et al, ) we showed that DC applications do not change the sag ratio between the peak and plateau R IN values of motoneurons subjected to polarization, indicating unaltered Ih current levels.…”

KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats

“… 1 – 5 It is known that KCNQ channels have potential therapeutic value by targeting their activity. 6 , 7 The differentially expressed KCNQ subunits have a direct role in regulating excitability of the neurons that they are distributed. 2 It has been anticipated that by targeting KCNQ channels for development of new drugs on neuronal excitability will be a breakthrough on improving neuronal diseases.…”

Adaptation of spontaneous activity in the developing visual cortex

“…Moreover, the timescale over which the threshold slides to prevent unbounded synaptic growth needs to be much faster than experimentally found [90]. Our proposed Hevent amplitude adaptation operates on the fast timescale of several spontaneous events found experimentally [26,62,50]. Hence, together with the better topography and the resulting event sparsification as a function of developmental stage that the Hebbian rule with adaptive H-events generates, we propose it as the more likely plasticity mechanism to refine receptive fields in the developing visual cortex.…”

“…Our adaptation mechanism is consistent with fast intrinsic plasticity operating on the timescale of several spontaneous events supported by many experimental studies. For instance, intrinsic excitability of spine motoneurons is depressed after brief but sustained changes in spinal cord network activity in neonatal mice [50]. Similarly, hippocampal pyramidal neurons also exhibit a rapid reduction of intrinsic excitability in response to sustained depolarizations lasting up to several minutes [62].…”

“…The activity trace η j might biophysically be implemented through a calcium-dependent signaling pathway that is activated upon sufficient burst depolarization and that is able to modulate a cell's excitability in the form of intrinsic plasticity [47,48,49]. A fast, activitydependent mechanism that decreases single-neuron excitability following a prolonged period of high network activity has been identified in spinal motor neurons of neonatal mice [50]. However, there might be other ways to implement this adaptation (see Discussion).…”