Evidence that increased Kcnj6 gene dose is necessary for deficits in behavior and dentate gyrus synaptic plasticity in the Ts65Dn mouse model of Down syndrome.
Down syndrome (DS), trisomy 21, is caused by increased dose of genes present on human chromosome 21 (HSA21). The gene-dose hypothesis argues that a change in the dose of individual genes or regulatory sequences on HSA21 is necessary for creating DS-related phenotypes, including cognitive impairment. We focused on a possible role for Kcnj6, the gene encoding Kir3.2 (Girk2) subunits of a G-protein-coupled inwardly-rectifying potassium channel. This gene resides on a segment of mouse Chromosome 16 that is present in one extra copy in the genome of the Ts65Dn mouse, a well-studied genetic model of DS. Kir3.2 subunit-containing potassium channels serve as effectors for a number of postsynaptic metabotropic receptors including GABAB receptors. Several studies raise the possibility that increased Kcnj6 dose contributes to synaptic and cognitive abnormalities in DS. To assess directly a role for Kcnj6 gene dose in cognitive deficits in DS, we produced Ts65Dn mice that harbor only 2 copies of Kcnj6 (Ts65Dn:Kcnj6++- mice). The reduction in Kcnj6 gene dose restored to normal the hippocampal level of Kir3.2. Long-term memory, examined in the novel object recognition test with the retention period of 24h, was improved to the level observed in the normosomic littermate control mice (2N:Kcnj6++). Significantly, both short-term and long-term potentiation (STP and LTP) was improved to control levels in the dentate gyrus (DG) of the Ts65Dn:Kcnj6++- mouse. In view of the ability of fluoxetine to suppress Kir3.2 channels, we asked if fluoxetine-treated DG slices of Ts65Dn:Kcnj6+++ mice would rescue synaptic plasticity. Fluoxetine increased STP and LTP to control levels. These results are evidence that increased Kcnj6 gene dose is necessary for synaptic and cognitive dysfunction in the Ts65Dn mouse model of DS. Strategies aimed at pharmacologically reducing channel function should be explored for enhancing cognition in DS.
Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: akleschevnikov@ucsd.edu.
Alexander M
AM
Kleschevnikov
Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Jessica
J
Yu
Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Jeesun
J
Kim
Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Academy of Biology and Biotechnology of Southern Federal University, 194/1 Stachki Str, Rostov-na-Donu 344090, Russian Federation.
Larisa V
LV
Lysenko
Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Zheng
Z
Zeng
The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Y Eugene
YE
Yu
Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
William C
WC
Mobley
D000818:Animals; D018891:Dentate Gyrus / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D018628:Gene Dosage / Q000502:physiology*; D008124:Locomotion / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse
Cognition; Down syndrome critical region; Fluoxetine; Genotype-phenotype relationship; Kcnj6; Kir3.2; Learning; Locomotor activity; Long-term potentiation; Mouse models; Novel object recognition; Synaptic plasticity; Ts65Dn; Y-maze