Knockin mice with Leu9'Ser alpha4-nicotinic receptors: substantia nigra dopaminergic neurons are hypersensitive to agonist and lost postnatally.

This study analyzes the electrophysiological cause and behavioral consequence of dopaminergic cell loss in a knockin mouse strain bearing hypersensitive nicotinic alpha4-receptor subunits ("L9'S mice"). Adult brains of L9'S mice show moderate loss of substantia nigra dopaminergic neurons and of striatal dopaminergic innervation. Amphetamine-stimulated locomotion is impaired, reflecting a reduction of dopamine stored in presynaptic vesicles. Recordings from dopaminergic neurons in L9'S mice show that 10 microM nicotine depolarizes cells and increases spiking rates in L9'S cells but hyperpolarizes and decreases spiking rates in wild-type (WT) cells. Thus dopaminergic neurons of L9'S mice have an excitatory response to nicotine which is qualitatively different from that of WT neurons. The cause of dopaminergic cell death is therefore probably an increased sensitivity to acetylcholine or choline of alpha4-containing nicotinic receptors. Hypersensitive excitatory stimulation during activation of alpha4-containing receptors provides the first evidence for cholinergic excitotoxicity as a cause of dopaminergic neuron death. This novel concept may be relevant to the pathophysiology of Parkinson disease.