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Genetic suppression of agrin reduces mania-like behavior in Na+ , K+ -ATPase α3 mutant mice
G S Kirshenbaum1, S J Clapcote, J Petersen
1Samuel Lunenfeld Research Institute, Mount Sinai Hospital Institute of Medical Science, University of Toronto, Toronto, ON, Canada. greershelby@gmail.com
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.
Insights
Reducing agrin, a synaptic proteoglycan, alleviates mania-like behaviors and normalizes circadian rhythms in Myshkin mice by restoring Na(+) ,K(+) -ATPase activity. This highlights agrin as a therapeutic target for neurological disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Myshkin mice, with a mutation in the neuron-specific Na(+) ,K(+) -ATPase α3 isoform, exhibit mania-like behaviors and altered circadian rhythms.
- Agrin, a synaptic proteoglycan, is hypothesized to inhibit Na(+) ,K(+) -ATPase α3 activity.
Purpose of the Study:
- To investigate if reducing agrin expression genetically can rescue mania-like behaviors in Myshkin mice.
- To determine the role of agrin in regulating Na(+) ,K(+) -ATPase activity and circadian rhythms.
Main Methods:
- Genetic knockout of agrin in Myshkin mice.
- Behavioral assessments including hyperambulation, holeboard exploration, anxiety-like behavior, and prepulse inhibition.
- Measurement of brain Na(+) ,K(+) -ATPase activity.
Main Results:
- Agrin suppression ameliorated hyperambulation, holeboard exploration, and risk-taking behavior, while improving prepulse inhibition and normalizing circadian period.
- In Myshkin mice, agrin suppression increased brain Na(+) ,K(+) -ATPase activity by 11 ± 4%.
- No significant change in Na(+) ,K(+) -ATPase activity was observed in wild-type mice with agrin suppression.
Conclusions:
- Agrin plays a crucial role in regulating mania-like behavior and circadian rhythms.
- Targeting agrin may offer a therapeutic strategy for mania and related neurological conditions characterized by reduced Na(+) ,K(+) -ATPase activity and neuronal hyperexcitability.
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