AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by beh...AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by behavioral tests,and the molecular mechanisms were investigated by patch-clamp experiments.RESULTS:The loss of Celsr3 led to ataxia-like behavior,accompanied by impaired miniature excitatory postsynaptic currents(mEPSCs)and postsynaptic long-term potentiation(LTP)in PCs.The cAMP activator forskolin ameliorated ataxia-like behavior and abrogated the mEPSCs impairment and LTP in model mice.Interestingly,the effects of forskolin could be blocked by SQ22536(a cAMP antagonist)and ESI-08(exchange protein activated by cAMP antagonist;Epac)but the H89(a PKA antagonist)could not block the effects.CONCLUSION:Celsr3 plays an important role in motor coordination by modulating synaptic function,and forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia.展开更多
基金Supported by the Natural Science Foundation of Chongqing Municipality,China(No.CSTB2022NSCQ-BHX0725)the National Natural Science Foundation of China(No.82401728).
文摘AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by behavioral tests,and the molecular mechanisms were investigated by patch-clamp experiments.RESULTS:The loss of Celsr3 led to ataxia-like behavior,accompanied by impaired miniature excitatory postsynaptic currents(mEPSCs)and postsynaptic long-term potentiation(LTP)in PCs.The cAMP activator forskolin ameliorated ataxia-like behavior and abrogated the mEPSCs impairment and LTP in model mice.Interestingly,the effects of forskolin could be blocked by SQ22536(a cAMP antagonist)and ESI-08(exchange protein activated by cAMP antagonist;Epac)but the H89(a PKA antagonist)could not block the effects.CONCLUSION:Celsr3 plays an important role in motor coordination by modulating synaptic function,and forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia.
