title: Genetic suppression of agrin reduces mania-like behavior in Na+ , K+ -ATPase α3 mutant mice.
abstract: 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.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital Institute of Medical Science, University of Toronto, Toronto, ON, Canada. greershelby@gmail.com
authors.forename: G S
authors.initials: GS
authors.lastname: Kirshenbaum
authors.forename: S J
authors.initials: SJ
authors.lastname: Clapcote
authors.forename: J
authors.initials: J
authors.lastname: Petersen
authors.forename: B
authors.initials: B
authors.lastname: Vilsen
authors.forename: M R
authors.initials: MR
authors.lastname: Ralph
authors.forename: J C
authors.initials: JC
authors.lastname: Roder
mesh_terms: D018171:Agrin / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism; D013489:Suppression, Genetic
chemical_list: D018171:Agrin; D000254:Sodium-Potassium-Exchanging ATPase