Deficiency in Na,K-ATPase α Isoform Genes Alters Spatial Learning, Motor Activity, and Anxiety in Mice

Abstract

Several disorders have been associated with mutations in Na,K-ATPase ␣ isoforms (rapid-onset dystonia parkinsonism, familial hemiplegic migraine type-2), as well as reduction in Na,K-ATPase content (depression and Alzheimer's disease), thereby raising the issue of whether haploinsufficiency or altered enzymatic function contribute to disease etiology. Three isoforms are expressed in the brain: the ␣1 isoform is found in many cell types, the ␣2 isoform is predominantly expressed in astrocytes, and the ␣3 isoform is exclusively expressed in neurons. Here we show that mice heterozygous for the ␣2 isoform display increased anxiety-related behavior, reduced locomotor activity, and impaired spatial learning in the Morris water maze. Mice heterozygous for the ␣3 isoform displayed spatial learning and memory deficits unrelated to differences in cued learning in the Morris maze, increased locomotor activity, an increased locomotor response to methamphetamine, and a 40% reduction in hippocampal NMDA receptor expression. In contrast, heterozygous ␣1 isoform mice showed increased locomotor response to methamphetamine and increased basal and stimulated corticosterone in plasma. The learning and memory deficits observed in the ␣2 and ␣3 heterozygous mice reveal the Na,K-ATPase to be an important factor in the functioning of pathways associated with spatial learning. The neurobehavioral changes seen in heterozygous mice suggest that these mouse models may be useful in future investigations of the associated human CNS disorders.

Mutation I810N in the α3 isoform of Na + ,K + -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

“…Heterozygous Myshkin males were crossed with female mice heterozygous for a point mutation in Atp1a3 intron 4 (Atp1a3 tm1Ling ) that show reduced ␣3 expression (21). No tm1Ling/Myk mice were detected among the 128 progeny at 4 weeks of age.…”

Distribution of the Na,K-ATPase α Subunit in the Rat Spiral Ganglion and Organ of Corti

“…The contribution of the NKAα1 and NKAα2 in maintaining the endocochlear potential is supported by the characterization of mice carrying deletions of these subunits. Although homozygous deletion of either NKAα1 or NKAα2 is lethal at birth, heterozygous deletions are viable (Moseley et al 2007). Despite normal cochlear morphology, NKAα1 +/− and NKAα2 +/− mice show reductions in the endocochlear potential and progressive, age-dependent hearing loss (Diaz et al 2007).…”

“…Homozygous deletion of NKAα3 is lethal; however, heterozygous deletion is viable (Moseley et al 2007). The hearing of NKAα3 +/− mice has not been reported.…”

Alternative Approaches to Modeling Hereditary Dystonias

“…Despite the identification of genes underlying many dystonias, the most common genetic manipulations (i.e, namely knockout of the suspected gene, knock-in of mutated versions of the causative human gene, and transgenics overexpressing the mutated human gene) have failed to recapitulate dystonia in rodents [49][50][51]. This is surprising because it is clear that rodents can exhibit dystonia, and in fact multiple strains of rodents suffer from dystonia due to spontaneous genetic mutations [52][53][54][55].…”

“…Unfortunately, mice homozygous for the ATP1A3 knockout are neonatal lethal and mice heterozygous for ATP1A3 show no dystonia [51,89].…”