title: Differential effects of alphaCaMKII mutation on hippocampal learning and changes in intrinsic neuronal excitability.
abstract: Alpha-calcium/calmodulin-dependent kinase II (alphaCaMKII) is central to synaptic plasticity but it remains unclear whether this kinase contributes to neuronal excitability changes, which are a cellular correlate of learning. Using knock-in mice with a targeted T286A mutation that prevents the autophosphorylation of alphaCaMKII (alphaCaMKII(T286A)), we studied the role of alphaCaMKII signaling in regulating hippocampal neuronal excitability during hippocampus-dependent spatial learning in the Morris water maze. Wild-type control mice showed increased excitability of CA1 pyramidal neurons, as assessed by a reduction in the postburst afterhyperpolarization (AHP), after spatial training in the water maze. Importantly, wild-type mice did not show AHP changes when they were exposed to the water maze without the escape platform and swam the same amount of time as the trained mice (swim controls), thus manifesting learning-specific increases in hippocampal CA1 excitability associated with spatial training. Meanwhile, alphaCaMKII(T286A) mice showed impairments in spatial learning but exhibited reduced levels of AHP that were similar to wild-type controls after water-maze training. Notably, both trained and swim-control groups of alphaCaMKII(T286A) mutants showed similar increased excitability, indicating that swimming by itself is enough to induce changes in excitability in the absence of normal alphaCaMKII function. This result demonstrates dissociation of alphaCaMKII-independent changes in intrinsic neuron excitability from learning and synaptic plasticity mechanisms, suggesting that increases in excitability per se are not perfectly correlated with learning. Our findings suggest that alphaCaMKII signaling may function to suppress learning-unrelated changes during training, thereby allowing hippocampal CA1 neurons to increase their excitability appropriately for encoding spatial memories.
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611-3008, USA. ohno@northwestern.edu
authors.forename: Masuo
authors.initials: M
authors.lastname: Ohno
authors.forename: Evgeny A
authors.initials: EA
authors.lastname: Sametsky
authors.forename: Alcino J
authors.initials: AJ
authors.lastname: Silva
authors.forename: John F
authors.initials: JF
authors.lastname: Disterhoft
mesh_terms: D000200:Action Potentials / Q000502:physiology / Q000528:radiation effects; D000409:Alanine / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D004558:Electric Stimulation / Q000379:methods; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology*; D066298:In Vitro Techniques; D007858:Learning / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000502:physiology* / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013912:Threonine / Q000235:genetics
chemical_list: D013912:Threonine; D017346:Protein Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D000409:Alanine