TY - JOUR
T1 - Selective cognitive deficits and reduced hippocampal brain-derived neurotrophic factor mRNA expression in small-conductance calcium-activated K+ channel deficient mice
AU - Jacobsen, J P R
AU - Redrobe, J P
AU - Hansen, H H
AU - Petersen, S
AU - Bond, C T
AU - Adelman, J P
AU - Mikkelsen, J D
AU - Mirza, N R
PY - 2009/9/29
Y1 - 2009/9/29
N2 - 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.
AB - 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.
KW - Animals
KW - Anti-Bacterial Agents/pharmacology
KW - Brain-Derived Neurotrophic Factor/genetics
KW - Cell Survival/genetics
KW - Cognition Disorders/genetics
KW - Cytoprotection/genetics
KW - Dentate Gyrus/metabolism
KW - Disease Models, Animal
KW - Down-Regulation/genetics
KW - Doxycycline/pharmacology
KW - Gene Expression Regulation/physiology
KW - Hippocampus/metabolism
KW - Maze Learning/drug effects
KW - Memory Disorders/genetics
KW - Memory, Short-Term/physiology
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - RNA, Messenger/metabolism
KW - Small-Conductance Calcium-Activated Potassium Channels/genetics
U2 - 10.1016/j.neuroscience.2009.05.062
DO - 10.1016/j.neuroscience.2009.05.062
M3 - Journal article
C2 - 19482064
SN - 0306-4522
VL - 163
SP - 73
EP - 81
JO - Neuroscience
JF - Neuroscience
IS - 1
ER -