The weaver mutation reverses the function of dopamine and GABA in mouse dopaminergic neurons

In the present study, we characterized the intrinsic electrophysiological p roperties and the membrane currents activated by dopamine (DA) D-2 and GABA (B) receptors in midbrain dopaminergic neurons, maintained in vitro in a sl ice preparation, from wild-type and homozygous weaver (wv/wv) mice. By usin g patch-clamp techniques, we found that membrane potential, apparent input resistance, and spontaneous firing of wv/wv dopaminergic neurons were simil ar to those of dopamine-containing cells recorded from nonaffected (+/+) an imals. 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 c urrent that reversed polarity at a membrane potential of approximately -30 mV. We suggest that the altered behavior of the receptor-operated wv G-prot ein-gated inwardly rectifying K+ channel 2 (GIRK2) might be related to the selective degeneration of the dopaminergic neurons. In addition, the wv GIR K2 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.