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

Abstract

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.

Unbalanced dendritic inhibition of CA1 neurons drives spatial-memory deficits in the Ts2Cje Down syndrome model

“…As expected, the ability of Ts2Cje mice to discriminate between novel and familiar objects was impaired. In contrast to previous reports, showing a recovery of NOR performance upon genetic normalization of Dyrk1a and Kcnj6 genes 25,28 , restoration of the Grik1 dosage in Ts Grik1 +/− littermates did not fully recover this impairment to the levels of euploid mice (Fig. 1e).…”

Spaced training improves learning in Ts65Dn and Ube3a mouse models of intellectual disabilities

“…Four widely studied behavioral paradigms with varying sensory and motor requirements and different neuroanatomical substrates were used in the present studies. These included (1) object location memory 38,66–72 , (2) novel object recognition 54,70,71,73–84 , (3) Morris water maze spatial learning 44,62,64,69,76,77,85–89 , and (4) rotarod motor learning 62,64,78,87,90–101 .…”

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

“…; Kleschevnikov et al. ). The role of trisomic Dyrk1a in pathology associated with DS has been supported by the numerous reports of deleterious phenotypes that occur due to both over and underexpression of Dyrk1a in transgenic Dyrk1a mouse models (Arque et al.…”