Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Mar;30(1):42-9.
doi: 10.1080/01677063.2016.1182525.

Deficits in Social Behavioral Tests in a Mouse Model of Alternating Hemiplegia of Childhood

Affiliations
Free PMC article

Deficits in Social Behavioral Tests in a Mouse Model of Alternating Hemiplegia of Childhood

Greer S Kirshenbaum et al. J Neurogenet. .
Free PMC article

Abstract

Social behavioral deficits have been observed in patients diagnosed with alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism and CAPOS syndrome, in which specific missense mutations in ATP1A3, encoding the Na(+), K(+)-ATPase α3 subunit, have been identified. To test the hypothesis that social behavioral deficits represent part of the phenotype of Na(+), K(+)-ATPase α3 mutations, we assessed the social behavior of the Myshkin mouse model of AHC, which has an I810N mutation identical to that found in an AHC patient with co-morbid autism. Myshkin mice displayed deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test. Chronic treatment with the mood stabilizer lithium enhanced nest building in wild-type but not Myshkin mice. In light of previous studies revealing a broad profile of neurobehavioral deficits in the Myshkin model - consistent with the complex clinical profile of AHC - our results suggest that Na(+), K(+)-ATPase α3 dysfunction has a deleterious, but nonspecific, effect on social behavior. By better defining the behavioral profile of Myshkin mice, we identify additional ATP1A3-related symptoms for which the Myshkin model could be used as a tool to advance understanding of the underlying neural mechanisms and develop novel therapeutic strategies.

Keywords: ATP1A3; mouse model; Alternating hemiplegia of childhood; social behavior.

Figures

Figure 1.
Figure 1.
Nest building behavior. (a) Representative examples of nest building by singly-housed Myk/+ (right) and +/+ (left) mice provided with a ripped up paper towel in a previous circadian rhythm study. (b) Nest quality score (0–4 scale) at 30 min, 60 min, 90 min, 3 h and 24 h after placement into a clean cage. Main effects of genotype (F(1, 44) = 73.86, p < 0.0001) and time (F(4, 44) = 8.66, p < 0.0001) were observed. (c) Percentage of nestlet shredded at 30 min, 60 min, 90 min, 3 h and 24 h after placement into a clean cage. Main effects of genotype (F(1, 44) = 74.12, p < 0.0001), time (F(4, 44) = 17.87, p < 0.0001) and genotype × time interaction (F(4, 44) = 7.73, p < 0.0001) were observed. (d) Height of nests at 24 h after placement into a clean cage. A main effect of genotype (F(1, 8) = 15.82, p < 0.01) was observed. Myk/+ mice (n = 6); +/+ mice (n = 6). *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001 versus +/+ mice.
Figure 2.
Figure 2.
Effects of chronic lithium treatment on nesting building. (a) Bouts of exploration and shredding of the nesting material. Main effects of genotype (F(1, 37) = 233.31, p < 0.0001), drug (F(1, 37) = 9.80, p < 0.01) and genotype × drug interaction (F(1, 37) = 5.39, p < 0.05) on bouts of shredding were observed. (b) Time spent exploring and shredding the nesting material over 5 min of observation in a clean cage. Main effects of genotype (F(1, 37) = 18.06, p < 0.0001) and drug (F(1, 37) = 4.39, p < 0.05) on time spent exploring, and a main effect of genotype (F(1, 37) = 101.27, p < 0.0001) on time spent shredding, were observed. (c) Nest quality score (0–4 scale) at 30 min, 60 min, 90 min, 3 h and 24 h after placement into a clean cage. Main effects of genotype (F(1, 212) = 595.26, p < 0.0001), drug (F(1, 212) = 9.87, p < 0.0001), time (F(4, 212) = 74.68, p < 0.0001), genotype × drug interaction (F(1, 212) = 24.82, p < 0.0001) and genotype × time interaction (F(4, 212) = 33.99, p < 0.0001) were observed. (d) Percentage of nestlet shredded at 30 min, 60 min, 90 min, 3 h and 24 h after placement into a clean cage. Main effects of genotype (F(1, 212) = 579.50, p < 0.0001), drug (F(1, 212) = 21.25, p < 0.0001), time (F(4, 212) = 100.05, p < 0.0001), genotype × drug interaction (F(1, 212) = 38.89, p < 0.0001), genotype × time interaction (F(4, 212) = 67.39, p < 0.0001), sex × drug interaction (F(1, 212) = 5.39, p < 0.05) and drug × time interaction (F(4, 212) = 5.69, p < 0.0001) were observed. (e) Height of nests at 24 h after placement into a clean cage. A main effect of genotype (F(1, 40) = 238.88, p < 0.0001) was observed. Myk/+ mice on standard diet (n = 15); Myk/+ mice on lithium diet (n = 11); +/+ mice on standard diet (n = 8); +/+ mice on lithium diet (n = 10). *p < 0.05; **p < 0.01; ****p < 0.0001 Myk/+ mice on standard diet versus +/+ mice on standard diet. # p < 0.05; ### p < 0.001 +/+ mice on lithium diet versus +/+ mice on standard diet.
Figure 3.
Figure 3.
Pup retrieval. Latency of Myk/+ (n = 8) and +/+ (n = 8) dams to return pup to the nest location. A main effect of genotype (F(1, 14) = 11.20, p < 0.01) was observed. **p < 0.01 Myk/+ mice versus +/+ mice.
Figure 4.
Figure 4.
Three-chamber social approach test. (a) Sociability phase: time spent by the subject exploring a novel adult male mouse (Stranger 1) or an empty container. A main effect of genotype (F(1, 14) = 5.98, p < 0.05) on time in contact with the novel mouse was observed. (b) Social Novelty phase: time spent by the subject exploring the mouse previously explored (Stranger 1) and a second novel adult male mouse (Stranger 2). A main effect of genotype (F(1, 14) = 26.71, p < 0.0001) on time in contact with Stranger 2 was observed. (c) Distance travelled (m) in the Sociability and Social Novelty phases of the test. There was no main effect of genotype or sex. Myk/+ mice (n = 8); +/+ mice (n = 10). **p < 0.01; ****p < 0.0001 versus +/+ mice. #### p < 0.0001 versus Stranger 1.

Similar articles

See all similar articles

Cited by 1 article

  • Na⁺, K⁺-ATPase Signaling and Bipolar Disorder.
    Lichtstein D, Ilani A, Rosen H, Horesh N, Singh SV, Buzaglo N, Hodes A. Lichtstein D, et al. Int J Mol Sci. 2018 Aug 7;19(8):2314. doi: 10.3390/ijms19082314. Int J Mol Sci. 2018. PMID: 30087257 Free PMC article. Review.

References

    1. Bailey K.R., Crawley J.N. 2009Anxiety-related behaviors in miceIn:Buccafusco J.J., editor. Methods of Behavior Analysis in Neuroscience 2nd edBoca Raton: CRC Press
    1. Benarroch E.E. Na+,K+-ATPase: functions in the nervous system and involvement in neurologic disease. Neurology. 2011;76:287–293. - PubMed
    1. Boelman C., Lagman-Bartolome A.M., MacGregor D.L., McCabe J., Logan W.J., Minassian B.A. Identical ATP1A3 mutation causes alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism phenotypes. Pediatric Neurology. 2014;51:850–853. - PubMed
    1. Clapcote S.J., Duffy S., Xie G., Kirshenbaum G., Bechard A.R., Schack V., Roder J.C. Mutation I810N in the α3 isoform of Na+,K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS. Proceedigs of the National Academy of Science USA. 2009;106:14085–14090. - PMC - PubMed
    1. Dard R., Mignot C., Durr A., Lesca G., Sanlaville D., Roze E., Mochel F. Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation. Developmental Medicine and Child Neurology. 2015;57:1183–1186. - PubMed

Publication types

Supplementary concepts

Feedback