Genetic suppression of agrin reduces mania-like behavior in Na+ , K+ -ATPase α3 mutant mice.

G S Kirshenbaum, S J Clapcote, J Petersen, B Vilsen, M R Ralph, J C Roder

Genes, brain, and behavior 2012 Jun

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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. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Citation

G S Kirshenbaum, S J Clapcote, J Petersen, B Vilsen, M R Ralph, J C Roder. Genetic suppression of agrin reduces mania-like behavior in Na+ , K+ -ATPase α3 mutant mice. Genes, brain, and behavior. 2012 Jun;11(4):436-43