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.

paper Cited Public

Authors: Kleschevnikov, Alexander M; Yu, Jessica; Kim, Jeesun; Lysenko, Larisa V; Zeng, Zheng; Yu, Y Eugene; Mobley, William C
Year: 2017
Journal: Neurobiology of disease
PMID: 28342823
DOI: 10.1016/j.nbd.2017.03.009
PMCID: PMC5446050

Fig. 1

Changes in body weight. The body weight was reduced in both Ts65Dn:Kcnj6+++ and Ts65Dn:Kcnj6++− vs. 2N:Kcnj6++ mice at all ages. There was no difference between the body weight of Ts65Dn:Kcnj6+++ vs. Ts65Dn:Kcnj6++− in young animals (1–4 months). However, the body weight was increased in older (5–6 mo and 9–12 mo) Ts65Dn:Kcnj6++− vs. Ts65Dn:Kcnj6+++ mice. The animal numbers and other statistical parameters are given in Table 1.

Fig. 2

Hippocampal levels of proteins. A. Level of Kir3.1 was not altered, while level of Kir3.2 was increased in Ts65Dn:Kcnj6+++ (n = 6) vs. 2N:Kcnj6++ (n = 5) samples. B. There was no difference in the levels of either Kir3.1 or Kir3.2 in Ts65Dn:Kcnj6++− (n = 5) vs. 2N:Kcnj6++ (n = 6) samples. C. Kir3.1 level was not different, but Kir3.2 was increased in Ts65Dn:Kcnj6+++ (n = 5) vs. Ts65Dn:Kcnj6++− (n = 6) mice.

Fig. 3

Spontaneous locomotion. A. Ambulatory distance was significantly increased in both Ts65Dn:Kcnj6+++ (n = 12) and Ts65Dn:Kcnj6++− (n = 14) vs. 2N:Kcnj6++ (n = 19) mice. No difference between Ts65Dn:Kcnj6+++ vs. Ts65Dn:Kcnj6++− mice was observed. B. Ambulatory time was also increased in both Ts65Dn:Kcnj6+++ and Ts65Dn:Kcnj6++− mice. C, D. Ambulatory distance and ambulatory time spent on periphery were greater in Ts65Dn:Kcnj6+++ vs. 2N:Kcnj6++ mice, but not different in Ts65Dn:Kcnj6++− vs. 2N:Kcnj6++ animals.

Fig. 4

Working memory and exploratory activity in the Y-maze. A. The rate of spontaneous alternations was reduced in both Ts65Dn:Kcnj6+++ (n = 12) and Ts65Dn:Kcnj6++− (n = 14) vs. 2N:Kcnj6++ (n = 19) mice. Reduction of Kcnj6 gene dose had no effect on performance of Ts65Dn mice (p = 0.84 for Ts65Dn:Kcnj6+++ vs. Ts65Dn:Kcnj6++−). B. Number of ‘arm entries’ during the Y-maze test was greater in Ts65Dn:Kcnj6+++ vs. 2N:Kcnj6++ mice. The number of arm entries was reduced in Ts65Dn:Kcnj6++− mice to the level of 2N:Kcnj6++ controls.

Fig. 5

Long-term memory. Performance in the novel object recognition test with a retention period of 24 h. A: Time for object exploration was not different between genotypes. B: The discrimination index was reduced in Ts65Dn:Kcnj6+++ (n = 12) vs. 2N:Kcnj6++ (n = 19) mice, but it was increased in Ts65Dn:Kcnj6++− (n = 14) mice to the level observed in 2N:Kcnj6++ control mice.

Fig. 6

Synaptic plasticity: effect of the Kcnj6 gene dose on STP and LTP in DG. A. Averaged changes in the initial slope of field EPSP during the experiment. B. Averaged values for STP (1–15 min) and LTP (30–60 min). STP and LTP were reduced in Ts65Dn:Kcnj6+++ (n = 8) vs. 2N:Kcnj6++ (n = 12) slices. Both parameters were normalized in slices from Ts65Dn:Kcnj6++− (n = 11) mice.

Fig. 7

Synaptic plasticity: Effect of fluoxetine on STP and LTP in DG. A. Averaged changes in the initial slope of field EPSP during the experiment. Application of fluoxetine or vehicle marked by the black line under the graph. B. Averaged values for STP (1–15 min) and LTP (30–60 min). Both STP and LTP were reduced in Ts65Dn (n = 14) vs. 2N (n = 13) slices. Fluoxetine increased both parameters in Ts65Dn slices (n = 10) to control levels, but did not affect these parameters in 2N slices (n = 7).

#	Section	Preview
40	Discussion	In rodents, Kir3.2 is present in the neocortex, cerebellum, hippocampus, and thalamus as early as p5…
41	Discussion	Hippocampus-dependent long-term memory is impaired both in DS (Carlesimo et al., 1997; Vicari et…
42	Discussion	In contrast to the evidence that increased Kcnj6 dose contributes to deficits in synaptic plasticity…
43	Discussion	Pharmacological strategies to combat the effect of Kcnj6 gene dose could be considered in an attempt…
44	Discussion	the Kir3.2 potassium channels. Fluoxetine improved both STP and LTP in the DG of Ts65Dn mice. Since…
45	Discussion	We conclude that increased expression of Kcnj6 necessarily contributes to abnormal synaptic…

Name	Type
2N local	cohort
2N controls local	cohort
2N:Kcnj6++ local	cohort
2N mice local	cohort
3-4 month old mice local	cohort
5HT-1A local	drug
A1 local	drug
AAV	drug
abnormal synaptic plasticity local	phenotype
alternation rate local	phenotype
Alzheimer’s disease	phenotype
Ambulatory distance local	phenotype
Ambulatory time local	phenotype
anxiety	phenotype
APP	gene
aprotinin	drug
arm entries local	phenotype
artificial cerebrospinal fluid	drug
BCA protein assay kit	drug
behavioral deficits	phenotype
Behavioral testing	phenotype
blindness	phenotype
body weight	phenotype
CaCl2	drug
cerebellum	anatomy
Clarity Western ECL Substrate local	drug
cognition	phenotype
compromised retrograde axonal transport of NGF local	phenotype
deficient cognition local	phenotype
deficient hippocampus-dependent long-term memory local	phenotype
degeneration of cholinergic neurons local	phenotype
dentate gyrus	anatomy
Dentate gyrus (DG) local	anatomy
diminished LTP local	phenotype
Discrimination index local	phenotype
Down syndrome	phenotype
Dp(16)1/+ model local	cohort
Dyrk1A	gene
EDTA	drug
enlargement of early endosomes local	phenotype
ethanol consumption	phenotype
exploratory activity local	phenotype
exploratory behavior	phenotype
fluoxetine	drug
Fluoxetine hydrochloride local	drug
GABA	phenotype
GABAB receptor	drug
GABAB receptor antagonist	drug
glucose	drug
glutamate	drug
goat anti-mouse secondary antibody local	drug
goat anti-rabbit IgG-HRP conjugate local	drug
hippocampal CA1 region	anatomy
hippocampus	anatomy
Humans with Down syndrome local	cohort
ImageJ	drug
increased GABAergic inhibition local	phenotype
Increased inhibition local	phenotype
intellectual disability	phenotype
isoflurane	drug
KCl	drug
KCNJ3	gene
Kcnj6	gene
Kcnj6++ local	variant
Kcnj6+/− local	variant
Kcnj6+/+ mice local	cohort
Kcnj6+/− mice local	cohort
KCNJ6 missense mutation (pore-forming domain) local	variant
Keppen-Lubinsky syndrome local	phenotype
Kir3.1 local	drug
Kir3.2 local	drug
Kir3.2 G to S missense mutation local	variant
Kir3.2 potassium channel local	drug
Kir3.2 three-nucleotide deletion local	variant
Laemmli Sample Buffer local	drug
leupeptin	drug
locomotion	phenotype
locomotor activity	phenotype
long-term memory	phenotype
long-term potentiation	phenotype
long-term potentiation (LTP)	phenotype
LTP	phenotype
M2 receptor	drug
MgSO4	drug
mice	cohort
microcephaly	phenotype
Middle Molecular Layer local	anatomy
Mouse genetic models local	cohort
Mouse genetic models of DS local	cohort
mouse monoclonal anti-β-actin primary antibody local	drug
Mx1	gene
Na3VO4	drug
Na-deoxycholate local	drug
NaF local	drug
NaH2PO4	drug
NaHCO3	drug
neocortex	anatomy
neurogenesis	phenotype
Neurophysiology local	phenotype
NGF	drug
novel object recognition memory local	phenotype
NP-40	drug
object recognition	phenotype
Pde6brd1 local	gene
Pde6brd1_homozygosity local	variant
pepstatin	drug
PMSF	drug
protease inhibitor cocktail	drug
Resting time local	phenotype
retinal degeneration local	phenotype
RIPA buffer	drug
serotonin	drug
severe developmental delay local	phenotype
short hairpin RNA against Dyrk1A local	drug
short-term potentiation	phenotype
Short-term potentiation (STP) local	phenotype
Sod1	gene
SOD1 transgenic mice local	cohort
spontaneous locomotor activity local	phenotype
stereotypy	phenotype
synaptic plasticity	phenotype
SYNJ1	gene
TBS-T local	drug
thalamus	anatomy
Thigmotaxis local	phenotype
Tris-Glycine gel local	drug
Tris-Glycine running buffer local	drug
Ts65Dn local	cohort
Ts65Dn:Kcnj6+++ local	cohort
Ts65Dn:Kcnj6++- local	cohort
Ts65Dn:Kcnj6++− local	cohort
Ts65Dn mice local	cohort
Ts65Dn mouse model local	cohort
Ts65Ds mouse local	cohort
Velocity local	phenotype
weaver phenotype local	phenotype
Weaver phenotype local	phenotype
working memory	phenotype
β-actin	gene

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In this knowledge base

Title	Year	PMID
Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons.	2023	36207584

External

Title	Authors	Journal	Year	Link
Identification of Neurite Outgrowth and Synaptic Plasticity-related Genes Showing Sustained Hypermethylation of Promoter Region in the Hippocampal Dentate Gyrus of Rats Exposed Maternally To Neurotoxicants To Induce Persistent Disruption of Hippocampal Neurogenesis.	Ojiro R et al.	—	2025	→
Amyloid-β oligomers trigger sex-dependent inhibition of GIRK channel activity in hippocampal neurons in mice.	Luo H et al.	—	2024	→
Domain-selective and sex-dependent regulation of learning and memory in mice by GIRK channel activity in CA1 pyramidal neurons of the dorsal hippocampus.	Luo H et al.	—	2024	→
Identifying the joint signature of brain atrophy and gene variant scores in Alzheimer's Disease.	Cruciani F et al.	—	2024	→
Lamivudine modulates the expression of neurological impairment-related genes and LINE-1 retrotransposons in brain tissues of a Down syndrome mouse model.	Borgognone A et al.	—	2024	→
Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model.	Llambrich S et al.	—	2024	→
Transcranial Direct Current Stimulation in neurogenetic syndromes: new treatment perspectives for Down syndrome?	Faralli A et al.	—	2024	→
Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons.	Popova D et al.	—	2023	→
Brain circuit pathology in Down syndrome: from neurons to neural networks.	Bartesaghi R	—	2023	→
Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model	Llambrich S et al.	—	2023	—
Potassium Channels in Parkinson's Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment.	Chen X et al.	—	2023	→
A Method for Bridging Population-Specific Genotypes to Detect Gene Modules Associated with Alzheimer's Disease.	Dai Y et al.	—	2022	→
Enhanced GIRK2 channel signaling in Down syndrome: A feasible role in the development of abnormal nascent neural circuits.	Kleschevnikov AM	—	2022	→
GABA<sub>B</sub> Receptors and Cognitive Processing in Health and Disease.	Vlachou S	—	2022	→
GIRK2 Channels in Down Syndrome and Alzheimer's Disease.	Kleschevnikov A	—	2022	→
Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model.	Sawa M et al.	—	2022	→
Neuronal G protein-gated K<sup>+</sup> channels.	Luo H et al.	—	2022	→
Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders.	Bartesaghi R et al.	—	2022	→
Cholinergic neurodegeneration in Alzheimer disease mouse models.	Shekari A et al.	—	2021	→
Nuclear Reorganization in Hippocampal Granule Cell Neurons from a Mouse Model of Down Syndrome: Changes in Chromatin Configuration, Nucleoli and Cajal Bodies.	Puente-Bedia A et al.	—	2021	→
Restoring neuronal chloride homeostasis with anti-NKCC1 gene therapy rescues cognitive deficits in a mouse model of Down syndrome.	Parrini M et al.	—	2021	→
Targeting increased levels of APP in Down syndrome: Posiphen-mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model.	Chen XQ et al.	—	2021	→
Therapeutic potential of targeting G protein-gated inwardly rectifying potassium (GIRK) channels in the central nervous system.	Jeremic D et al.	—	2021	→
A missense point mutation in nerve growth factor (NGF<sup>R100W</sup>) results in selective peripheral sensory neuropathy.	Yang W et al.	—	2020	→
Genetic and epigenetic pathways in Down syndrome: Insights to the brain and immune system from humans and mouse models.	Yu YE et al.	—	2020	→
Intellectual Disability and Potassium Channelopathies: A Systematic Review.	Kessi M et al.	—	2020	→
Modeling Down syndrome in animals from the early stage to the 4.0 models and next.	Muñiz Moreno MDM et al.	—	2020	→
Repeated Methylglyoxal Treatment Depletes Dopamine in the Prefrontal Cortex, and Causes Memory Impairment and Depressive-Like Behavior in Mice.	Szczepanik JC et al.	—	2020	→
Down syndrome.	Rafii MS et al.	—	2019	→
Spaced training improves learning in Ts65Dn and Ube3a mouse models of intellectual disabilities.	Lauterborn JC et al.	—	2019	→
Unbalanced dendritic inhibition of CA1 neurons drives spatial-memory deficits in the Ts2Cje Down syndrome model.	Valbuena S et al.	—	2019	→
Developmental excitatory-to-inhibitory GABA polarity switch is delayed in Ts65Dn mice, a genetic model of Down syndrome.	Lysenko LV et al.	—	2018	→
GABAergic over-inhibition, a promising hypothesis for cognitive deficits in Down syndrome.	Zorrilla de San Martin J et al.	—	2018	→
Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits.	Stringer M et al.	—	2017	→