The M-Current Inhibitor XE991 Decreases the Stimulation Threshold for Long-Term Synaptic Plasticity in Healthy Mice and in Models of Cognitive Disease A ´ ngela Fonta ´n-Lozano, Irene Sua ´rez-Pereira, Jose ´ Marı ´a Delgado-Garcı ´a, and A ´ ngel Manuel Carrio ´n * ABSTRACT: Aging, mental retardation, number of psychiatric and neurological disorders are all associated with learning and memory impairments. As the underlying causes of such conditions are very het- erogeneous, manipulations that can enhance learning and memory in mice under different circumstances might be able to overcome the cog- nitive deficits in patients. The M-current regulates neuronal excitability and action potential firing, suggesting that its inhibition may increase cognitive capacities. We demonstrate that XE991, a specific M-current blocker, enhances learning and memory in healthy mice. This effect may be achieved by altering basal hippocampal synaptic activity and by diminishing the stimulation threshold for long-term changes in synaptic efficacy and learning-related gene expression. We also show that train- ing sessions regulate the M-current by transiently decreasing the levels of KCNQ/Kv7.3 protein, a pivotal subunit for the M-current. Further- more, we found that XE991 can revert the cognitive impairment associ- ated with acetylcholine depletion and the neurodegeneration induced by kainic acid. Together, these results show that inhibition of the M-cur- rent as a general strategy may be useful to enhance cognitive capacities in healthy and aging individuals, as well as in those with neurodegenera- tive diseases. V V C 2009 Wiley-Liss, Inc. KEY WORDS: synaptic plasticity; learning; memory; LTP; XE911; gene expression; kainate-induced neurodegeneration INTRODUCTION Among voltage-gated K 1 currents, the M-current is a primary trans- ducer of changes in the chemical composition of the extracellular envi- ronment into modifications of intrinsic neuronal properties. The M-cur- rent was first identified in amphibian peripheral neurons (Brown and Adams, 1980) but later, it was also found in the mammalian peripheral and central nervous system (Halliwell and Adams, 1982; Brown, 1988). It is a low threshold, slowly activating and deactivating, and noninacti- vating voltage-dependent K 1 current that limits repetitive firing and causes spike-frequency adaptation (Rowaski, 2000). Most of the bio- physical and pharmacological properties of the M-cur- rent are recapitulated upon heteromeric expression of K 1 channel subunits encoded by members of the KCNQ/Kv7 gene family. Within that family, the KCNQ/Kv7.2 and three subunits playing a dominant role at most neuronal sites (Wang et al., 1998; Cooper et al., 2000), although KCNQ/Kv7.5 transcripts have also been ubiquitously detected in human brain (Lerche et al., 2000). The kinetic properties of the M-current are sugges- tive of a role in regulating neuronal excitability. Suppression of the M-current by muscarinic agonists or by selective blockers of the M-channels, such as linopirdine (Aiken et al., 1995; Costa and Brown, 1997; Lamas et al., 1997; Schnee and Brown, 1998) or XE991 (Zaczek et al., 1998), causes an increase in intrinsic excitability. Indeed, the suppression of the M-current shifts the firing mode of hippocampal CA1 pyramidal cells from regular firing to burst firing by augmenting the spike after-depolarization (Yue and Yaari, 2004), as well as by reducing the intrinsic sub- threshold theta resonance (Hu et al., 2002; Peters et al., 2005). As spike bursts and subthreshold mem- brane potential oscillations are believed to be impor- tant for synaptic plasticity (Magee and Johnston, 1997; Thomas et al., 1998) and network oscillation (Buzsa ´ki, 2002; Franse ´n et al., 2004), the M-current may not only be important to control excitability but also for brain functions such as memory. On the basis of the physiological role of the M-cur- rent, it has been postulated that M-current suppressors may potentially enhance cognitive processes in certain circumstances (Brioni et al., 1993; Jentsch, 2000 for a review). Here we show that systemic administration of the M-current inhibitor, XE991, facilitates learning and memory in healthy mice by decreasing the stimu- lation threshold for certain cognitive processes and for long-term changes in synaptic efficacy. In addition, this inhibitor induces the expression of bdnf and arc. Furthermore, we show that synaptic activity induced by training provokes a transient decrease of KCNQ/ Kv7.3 in the hippocampus and perirhinal cortex. Finally, systemic administration of XE991 recovered cognitive deficits induced by transient cholinergic depletion and by the neurodegeneration induced by Divisio ´ n de Neurociencias, Universidad Pablo de Olavide de Sevilla, Carretera de Utrera Km. 1, Sevilla, Spain Additional Supporting Information may be found in the online version of this article. Grant sponsor: Junta de Andalucı ´a; Grant number: CVI-122; Grant spon- sor: DGICYT; Grant number: BFI2002-00936. *Correspondence to: A ´ ngel M. Carrio ´n, Divisio ´n de Neurociencias, Universidad Pablo de Olavide, Carretera de Utrera Km. 1, Sevilla 41013, Spain. E-mail: amancar@upo.es Accepted for publication 4 September 2009 DOI 10.1002/hipo.20717 Published online 17 November 2009 in Wiley Online Library (wileyonlinelibrary.com). HIPPOCAMPUS 21:22–32 (2011) V V C 2009 WILEY-LISS, INC.