The M-current inhibitor XE991 decreases the stimulation threshold for long-term synaptic plasticity in healthy mice and in models of cognitive disease.
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 heterogeneous, manipulations that can enhance learning and memory in mice under different circumstances might be able to overcome the cognitive 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 training sessions regulate the M-current by transiently decreasing the levels of KCNQ/Kv7.3 protein, a pivotal subunit for the M-current. Furthermore, we found that XE991 can revert the cognitive impairment associated with acetylcholine depletion and the neurodegeneration induced by kainic acid. Together, these results show that inhibition of the M-current as a general strategy may be useful to enhance cognitive capacities in healthy and aging individuals, as well as in those with neurodegenerative diseases.
Fontán-Lozano
Angela
A
División de Neurociencias, Universidad Pablo de Olavide de Sevilla, Carretera de Utrera Km. 1, Seville, Spain.
Suárez-Pereira
Irene
I
Delgado-García
José María
JM
Carrión
Angel Manuel
AM
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D003072:Cognition Disorders / Q000503:physiopathology*; D004195:Disease Models, Animal; D004594:Electrophysiology; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D051659:KCNQ3 Potassium Channel / Q000096:biosynthesis / Q000187:drug effects*; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D051659:KCNQ3 Potassium Channel; D026902:Potassium Channel Blockers