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The Journal of Neuroscience, August 15, 2000, 20(16):6013-6020

The weaver Mutation Reverses the Function of Dopamine and GABA in Mouse Dopaminergic Neurons

Ezia Guatteo¹, Francesca R. Fusco¹, Patrizia Giacomini³, Giorgio Bernardi^{1, 2}, and Nicola B. Mercuri^{1, 2}

¹ Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, 00179 Rome, Italy, ² Clinica Neurologica, Università di Tor Vergata, 00173 Rome, Italy, and ³ Clinica Neurologica, Università di Roma La Sapienza, 00161 Rome, Italy

In the present study, we characterized the intrinsic electrophysiological properties and the membrane currents activated by dopamine (DA) D₂ and GABA_B receptors in midbrain dopaminergic neurons, maintained in vitro in a slice preparation, from wild-type and homozygous weaver (wv/wv) mice. By using patch-clamp techniques, we found that membrane potential, apparent input resistance, and spontaneous firing of wv/wv dopaminergic neurons were similar to those of dopamine-containing cells recorded from nonaffected (+/+) animals.

More interestingly, the wv/wv neurons were excited rather than inhibited by dopamine and the GABA_B agonist baclofen. This neurotransmitter-mediated excitation was attributable to the activation of a G-protein-gated inward current that reversed polarity at a membrane potential of approximately 30 mV. We suggest that the altered behavior of the receptor-operated wv G-protein-gated inwardly rectifying K⁺ channel 2 (GIRK2) might be related to the selective degeneration of the dopaminergic neurons. In addition, the wv GIRK2 would not only suppress the autoreceptor-mediated feedback inhibition of DA release but could also establish a feedforward mechanism of DA release in the terminal fields.

Key words: substantia nigra; dopamine; baclofen; inwardly rectifying K⁺ channels; weaver mouse; electrophysiology; dopamine-related disorders

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20166013-08$05.00/0

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