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
| Autor: | Jeesun Kim, Y. Eugene Yu, Larisa V. Lysenko, William C. Mobley, Jessica Yu, Zheng Zeng, Alexander M. Kleschevnikov |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Gene Dosage 129 Strain Hippocampal formation Mouse models Transgenic Mice 0302 clinical medicine Cognition Down syndrome critical region 2.1 Biological and endogenous factors Aetiology Neuronal Plasticity Kcnj6 Long-term potentiation Mental Health Neurology Genotype-phenotype relationship Locomotion Locomotor activity Kir3.2 Mice 129 Strain Intellectual and Developmental Disabilities (IDD) 1.1 Normal biological development and functioning Novel object recognition Clinical Sciences Mice Transgenic Biology GABAB receptor Gene dosage Ts65Dn Synaptic plasticity Article lcsh:RC321-571 03 medical and health sciences Underpinning research Fluoxetine Genetic model Behavioral and Social Science Acquired Cognitive Impairment Genetics Learning Animals Maze Learning lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Y-maze Neurology & Neurosurgery Animal Dentate gyrus Neurosciences Brain Disorders Disease Models Animal 030104 developmental biology Metabotropic receptor G Protein-Coupled Inwardly-Rectifying Potassium Channels Disease Models Dentate Gyrus Down Syndrome Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Neurobiology of Disease, Vol 103, Iss, Pp 1-10 (2017) |
| Popis: | 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 24 h, 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. |
| Databáze: | OpenAIRE |
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