• Agrin;
  • Agrn;
  • Atp1a3;
  • bipolar disorder;
  • circadian rhythm;
  • mania;
  • mutant mouse;
  • Na+;
  • K+-ATPase alpha3

Myshkin mice heterozygous for an inactivating mutation in the neuron-specific Na+,K+-ATPase α3 isoform show behavior analogous to mania, including an abnormal endogenous circadian period. Agrin is a proteoglycan implicated as a regulator of synapses that has been proposed to inhibit activity of Na+,K+-ATPase α3. We examined whether the mania-related behavior of Myshkin mice could be rescued by a reduction in the expression of agrin through genetic knockout. The suppression of agrin reduced hyperambulation and holeboard exploration, restored anxiety-like behavior (or reduced risk-taking behavior), improved prepulse inhibition and shortened the circadian period. Hence, agrin is important for regulating mania-like behavior and circadian rhythms. In Myshkin mice, the suppression of agrin increased brain Na+,K+-ATPase activity by 11 ± 4%, whereas no effect on Na+,K+-ATPase activity was detected when agrin was suppressed in mice without the Myshkin mutation. These results introduce agrin as a potential therapeutic target for the treatment of mania and other neurological disorders associated with reduced Na+,K+-ATPase activity and neuronal hyperexcitability.