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GDNF acutely modulates excitability and A-type K+ channels in midbrain dopaminergic neurons

Abstract

Glial cell line-derived neurotrophic factor (GDNF) prevents lesion-induced death of midbrain dopaminergic neurons, but its function in normal brain remains uncertain. Here we show that GDNF acutely and reversibly potentiated the excitability of cultured midbrain neurons by inhibiting transient A-type K+ channels. The effects of GDNF were limited to large, tyrosine hydroxylase (TH)-positive dopaminergic neurons, and were mediated by mitogen associated protein (MAP) kinase. Application of GDNF also elicited a MAP kinase-dependent enhancement of the excitability in dopaminergic neurons in midbrain slice. These results demonstrate an acute regulation of GDNF on ion channels and its underlying signaling mechanism, and reveal an unexpected role of GDNF in normal midbrain dopaminergic neurons.

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Figure 1: GDNF modulation of membrane potential and firing behavior of cultured midbrain neurons.
Figure 2: GDNF suppresses A-type potassium currents (IA).
Figure 3: Pharmacological and kinetic analysis of GDNF modulation of IA.
Figure 4: Activation of MAP kinase by GDNF or other agents in cultured midbrain neurons.
Figure 5: Role of MAP kinase in GDNF modulation of neuronal excitability and A-currents.
Figure 6: Effect of GDNF on the excitability of dopaminergic neurons in midbrain slices.

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Acknowledgements

We thank C. McBain, J.-f. Zhang and J. Yang for discussions and comments on the manuscript. This work is supported in part by a grant from Shanghai Science and Technology Commission.

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Correspondence to Bai Lu.

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Yang, F., Feng, L., Zheng, F. et al. GDNF acutely modulates excitability and A-type K+ channels in midbrain dopaminergic neurons. Nat Neurosci 4, 1071–1078 (2001). https://doi.org/10.1038/nn734

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