title: Increasing SK2 channel activity impairs associative learning.
abstract: Enhanced intrinsic neuronal excitability of hippocampal pyramidal neurons via reductions in the postburst afterhyperpolarization (AHP) has been hypothesized to be a biomarker of successful learning. This is supported by considerable evidence that pharmacologic enhancement of neuronal excitability facilitates learning. However, it has yet to be demonstrated that pharmacologic reduction of neuronal excitability restricted to the hippocampus can retard acquisition of a hippocampus-dependent task. Thus, the present study was designed to address this latter point using a small conductance potassium (SK) channel activator NS309 focally applied to the dorsal hippocampus. SK channels are important contributors to intrinsic excitability, as measured by the medium postburst AHP. NS309 increased the medium AHP and reduced excitatory postsynaptic potential width of CA1 neurons in vitro. In vivo, NS309 reduced the spontaneous firing rate of CA1 pyramidal neurons and impaired trace eyeblink conditioning in rats. Conversely, trace eyeblink conditioning reduced levels of SK2 channel mRNA and protein in the hippocampus. Therefore, the present findings indicate that modulation of SK channels is an important cellular mechanism for associative learning and further support postburst AHP reductions in hippocampal pyramidal neurons as a biomarker of successful learning.
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Bridget M
authors.initials: BM
authors.lastname: McKay
authors.forename: M Matthew
authors.initials: MM
authors.lastname: Oh
authors.forename: Roberto
authors.initials: R
authors.lastname: Galvez
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Burgdorf
authors.forename: Roger A
authors.initials: RA
authors.lastname: Kroes
authors.forename: Craig
authors.initials: C
authors.lastname: Weiss
authors.forename: John P
authors.initials: JP
authors.lastname: Adelman
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Moskal
authors.forename: John F
authors.initials: JF
authors.lastname: Disterhoft
mesh_terms: D000818:Animals; D001245:Association Learning / Q000187:drug effects / Q000502:physiology*; D001767:Blinking / Q000187:drug effects / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D010091:Oximes / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000096:biosynthesis*
chemical_list: C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D007211:Indoles; C496899:Kcnn2 protein, rat; D010091:Oximes; D051640:Small-Conductance Calcium-Activated Potassium Channels