Selective cognitive deficits and reduced hippocampal brain-derived neurotrophic factor mRNA expression in small-conductance calcium-activated K+ channel deficient mice.
Small-conductance calcium-activated K(+) channels 1-3 (SK1-3) are important for neuronal firing regulation and are considered putative CNS drug targets. For instance non-selective SK blockers improve performance in animal models of cognition. The SK subtype(s) involved herein awaits identification and the question is difficult to address pharmacologically due to the lack of subtype-selective SK-channel modulators. In this study, we used doxycycline-induced conditional SK3-deficient (T/T) mice to address the cognitive consequences of selective SK3 deficiency. In T/T mice SK3 protein is near-eliminated from the brain following doxycycline treatment. We tested T/T and wild type (WT) littermate mice in five distinct learning and memory paradigms. In Y-maze spontaneous alternations and five-trial inhibitory avoidance the performance of T/T mice was markedly inferior to WT mice. In contrast, T/T and WT mice performed equally well in passive avoidance, object recognition and the Morris water maze. Thus, some aspects of working/short-term memory are disrupted in T/T mice. Using in situ hybridization, we further found the cognitive deficits in T/T mice to be paralleled by reduced brain-derived neurotrophic factor (BDNF) mRNA expression in the dentate gyrus and CA3 of the hippocampus. BDNF mRNA levels in the frontal cortex were not affected. BDNF has been crucially implicated in many cognitive processes. Hence, the biological substrate for the cognitive impairments in T/T mice could conceivably entail reduced trophic support of the hippocampus.
Jacobsen
J P R
JP
Department of In Vivo Pharmacology, Neurosearch A/S, Ballerup, Denmark. j.jacobsen@cellbio.duke.edu
Redrobe
J P
JP
Hansen
H H
HH
Petersen
S
S
Bond
C T
CT
Adelman
J P
JP
Mikkelsen
J D
JD
Mirza
N R
NR
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D019610:Cytoprotection / Q000235:genetics; D018891:Dentate Gyrus / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics*
D000900:Anti-Bacterial Agents; D019208:Brain-Derived Neurotrophic Factor; C496900:Kcnn3 protein, mouse; D012333:RNA, Messenger; D051640:Small-Conductance Calcium-Activated Potassium Channels; D004318:Doxycycline