Activity-dependent depression of the spike after-depolarization generates long-lasting intrinsic plasticity in hippocampal CA3 pyramidal neurons

JT Brown, AD Randall

Research output: Contribution to journalArticle (Academic Journal)peer-review

56 Citations (Scopus)


Persistent plastic changes to the intrinsic excitability of neurons have substantial implications for computational processing within the CNS. We have identified and characterized a novel long-lasting form of intrinsic plasticity in hippocampal CA3 pyramidal cells. Although the patterns of action potential firing elicited in this cell population by depolarizing current injections exhibited considerable diversity, practically all cells produced an initial high frequency (>100 Hz) burst of two to five spikes. This burst involved conductances that were responsible for the prominent spike afterdepolarization of CA3 pyramids. Long-lasting changes in the firing behaviour of CA3 cells were produced by conditioning stimuli (CS) consisting of either periods of depolarization in voltage clamp or periods of short (2 or 4 spikes) high frequency (circa 100 Hz) burst firing at 5 or 10 Hz. CS-induced changes included substantial prolongation of the first inter-spike interval and increased spike jitter. Similar CS-induced changes were seen when the test stimulus used to elicit firing resembled a glutamatergic EPSC. In line with this, a long-lasting depression of the ADP was elicited by the same CS that altered firing patterns of CA3 cells. Conditioning-induced changes in both spiking patterns and ADP amplitude were blocked by buffering intracellular Ca2+ with BAPTA. Furthermore, the Kv7 channel blocker XE991, a cognitive enhancer, both enhanced the ADP and completely eliminated its conditioning-induced depression. These findings indicate that a persistent enhancement of Kv7 channels, following a transient increase in cytoplasmic Ca2+, results in a prolonged depression of the ADP in CA3 pyramidal neurones. Previous SectionNext SectionIntrinsic plasticity is a form of neuronal plasticity that concerns CS-induced changes to core membrane properties of neurons that in turn affect their subsequent electrical responsiveness. Like synaptic plasticity, with which it is often closely entwined, intrinsic plasticity occurs in many forms covering a time scale from a few milliseconds to hours and very likely much longer. Intrinsic plasticity can be induced by the cell's own patterns of electrical activity (Egorov et al. 2002) or can arise from external influences including synaptic activity (Aizenman & Linden, 2000; Mellor et al. 2002; Sourdet et al. 2003; Fan et al. 2005; Xu et al. 2005). Furthermore, plastic changes to intrinsic neuronal properties can also arise as a consequence of a pathological environment (Chen et al. 2001; Wellmer et al. 2002). There is a growing understanding that long lasting changes in intrinsic neuronal excitability have the potential to play key roles in experience-dependent learning and memory (Disterhoft et al. 1986; Coulter et al. 1989; Moyer et al. 1996; McEchron et al. 2001; Zhang & Linden, 2003). Spike after-potentials, i.e. after-hyperpolarizations (AHPs) and after-depolarizations (ADPs), play an important role in shaping neuronal firing patterns (Storm, 1987; Williams & Stuart, 1999; Yue & Yaari, 2004; Gu et al. 2005; Bean, 2007). The mechanisms and functions of the ADP in hippocampal pyramidal neurons have received growing attention in recent years (Yue & Yaari, 2004; Metz et al. 2005; Yue et al. 2005; Vervaeke et al. 2006; Kaczorowski et al. 2007; Metz et al. 2007; Chen & Yaari, 2008). One membrane conductance that appears to play an important role in the regulation of the ADP is that mediated by Kv7/KCNQ/M-channels (known hereafter as Kv7 channels) (Yue & Yaari, 2004; Vervaeke et al. 2006; Yue & Yaari, 2006). Kv7 channels are thought to underlie the neuronal M current (IM) (Wang et al. 1998), a slowly activating, non-inactivating K+ conductance which is often active at membrane potentials around those observed in resting CNS neurons (Brown & Adams, 1980). Blockade of Kv7 channels enhances the ADP, whereas enhancing activation gating of Kv7 channels suppresses the ADP, resulting in corresponding changes to neuronal firing behaviour (Yue & Yaari, 2004; Vervaeke et al. 2006). Despite their important role controlling neuronal output, there are surprisingly few reports of persistent plastic changes to spike after-potentials. Both pharmacological and synaptic activation of group I metabotropic glutamate receptors (Sourdet et al. 2003; Ireland et al. 2004) and kainate receptors (Melyan et al. 2002, 2004) can induce long term modulation of AHPs. Recently, a millisecond scale enhancement of the ADP that arises from acute Ca2+-depedent inhibition Kv7 channels has been described in CA1 pyramidal cells (Chen & Yaari, 2008). To date, however, there have been no reports of long-term plastic changes to the ADP, and associated persistent alterations to neuronal firing and output. In this study we describe how CA3 neuron firing patterns can undergo a radical and long-lasting reconfiguration in response to conditioning stimuli that are pertinent to both the physiological and patho-physiological activity of these cells. This novel, persistent form of intrinsic plasticity results in changes to spike frequency, attenuation and jitter. This change is associated with, and arises from, a lasting depression of the ADP. This modification of the ADP is entirely dependent on the presence of functional Kv7 channels, suggesting that IM plays a previously unreported and pivotal role in long-term neuronal plasticity.
Translated title of the contributionActivity-dependent depression of the spike after-depolarization generates long-lasting intrinsic plasticity in hippocampal CA3 pyramidal neurons
Original languageEnglish
Pages (from-to)1265 - 1281
Number of pages17
JournalJournal of Physiology
Early online date26 Jan 2009
Publication statusPublished - 15 Mar 2009

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