TY - JOUR
T1 - Cognitive deficits caused by a disease-mutation in the α3 Na(+)/K(+)-ATPase isoform.
AU - Holm, Thomas Hellesøe
AU - Isaksen, Toke Jost
AU - Pedersen, Simon Glerup
AU - Heuck, Anders
AU - Bøttger, Pernille
AU - Füchtbauer, Ernst-Martin
AU - Nedergaard, Steen Torben
AU - Nyengaard, Jens Randel
AU - Andreasen, Mogens
AU - Nissen, Poul
AU - Lykke-Hartmann, Karin
PY - 2016
Y1 - 2016
N2 - The Na
+/K
+ -ATPases maintain Na
+ and K
+ electrochemical gradients across the plasma membrane, a prerequisite for electrical excitability and secondary transport in neurons. Autosomal dominant mutations in the human ATP1A3 gene encoding the neuron-specific Na
+/K
+-ATPase α
3 isoform cause different neurological diseases, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) with overlapping symptoms, including hemiplegia, dystonia, ataxia, hyperactivity, epileptic seizures, and cognitive deficits. Position D801 in the α
3 isoform is a mutational hotspot, with the D801N, D801E and D801V mutations causing AHC and the D801Y mutation causing RDP or mild AHC. Despite intensive research, mechanisms underlying these disorders remain largely unknown. To study the genotype-to-phenotype relationship, a heterozygous knock-in mouse harboring the D801Y mutation (α
3+/D801Y) was generated. The α 3
+/D801Y mice displayed hyperactivity, increased sensitivity to chemically induced epileptic seizures and cognitive deficits. Interestingly, no change in the excitability of CA1 pyramidal neurons in the α 3
+/D801Y mice was observed. The cognitive deficits were rescued by administration of the benzodiazepine, clonazepam, a GABA positive allosteric modulator. Our findings reveal the functional significance of the Na
+/K
+-ATPase α 3 isoform in the control of spatial learning and memory and suggest a link to GABA transmission.
AB - The Na
+/K
+ -ATPases maintain Na
+ and K
+ electrochemical gradients across the plasma membrane, a prerequisite for electrical excitability and secondary transport in neurons. Autosomal dominant mutations in the human ATP1A3 gene encoding the neuron-specific Na
+/K
+-ATPase α
3 isoform cause different neurological diseases, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) with overlapping symptoms, including hemiplegia, dystonia, ataxia, hyperactivity, epileptic seizures, and cognitive deficits. Position D801 in the α
3 isoform is a mutational hotspot, with the D801N, D801E and D801V mutations causing AHC and the D801Y mutation causing RDP or mild AHC. Despite intensive research, mechanisms underlying these disorders remain largely unknown. To study the genotype-to-phenotype relationship, a heterozygous knock-in mouse harboring the D801Y mutation (α
3+/D801Y) was generated. The α 3
+/D801Y mice displayed hyperactivity, increased sensitivity to chemically induced epileptic seizures and cognitive deficits. Interestingly, no change in the excitability of CA1 pyramidal neurons in the α 3
+/D801Y mice was observed. The cognitive deficits were rescued by administration of the benzodiazepine, clonazepam, a GABA positive allosteric modulator. Our findings reveal the functional significance of the Na
+/K
+-ATPase α 3 isoform in the control of spatial learning and memory and suggest a link to GABA transmission.
UR - http://www.scopus.com/inward/record.url?scp=84984656723&partnerID=8YFLogxK
U2 - 10.1038/srep31972
DO - 10.1038/srep31972
M3 - Journal article
C2 - 27549929
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
IS - 31972
M1 - 31972
ER -