The Na,K-ATPase is composed of multiple isoforms and the isoform distribution varies with the tissue and during development. The α1 isoform for example, is the major isoform in the kidney and many other tissues, while the α2 isoform is the predominate one in skeletal muscle. All three isoforms are found in the brain although in adult rodent brain, the α3 isoform is located essentially in neurons while the α2 isoform is found in astrocytes and some limited neuronal populations. Interestingly the α4 isoform is found exclusively in the mid region of the sperm tail. The distribution of the isoforms of the Na,K-ATPase has been extensively studied in many tissues and during development. The examples cited above provide some indication to the diversity of Na,K-ATPase isoform expression. In order to understand the significance of this distribution, we have developed animals which lack the α1, α2, and α3 isoforms. It is anticipated that these studies will provide insight into the role that these isoforms play in driving various biological processes in specific tissues. Here we describe some of our studies which deal with the behavioral aspects of the α1, α2, and α3 deficient mice, particularly those that are haploinsufficient in one isoform i.e. lacking one functional gene for the α1, α2, or α3 isoforms. Such studies are important as two human diseases are associated with deficiency in the α2 and α3 isoforms. These are Familial Hemiplegic Migraine type 2 and Rapid-Onset Dystonia Parkinsonism, these diseases result from α2 and α3 isoform haploinsufficiency, respectively. We find that the haploinsufficiency of both α2 and α3 isoforms result in behavioral defects.