Homeostatic regulation of dopaminergic neurons without dopamine.

A n astonishing number of psychomotor disorders stem from alterations of the function of brain neurons that release or respond to the neurotransmitter dopamine. Synthesized from the amino acid tyrosine, dopamine is implicated in drug abuse, attention deficit hyperactivity disorder, Tourette’s syndrome, dystonia, schizophrenia, and Parkinson’s disease (PD), where the control of internally generated movement or thought is disturbed (1). In PD, dopaminergic neurons in a region of the mesencephalon, the substantia nigra pars compacta, stop releasing dopamine and eventually die, leading to the emergence of bradykinesia, tremor, and rigidity (2). The neural adaptations in target structures, like the striatum, that accompany the gradual loss of dopaminergic neurons and the symptoms of the disease are beginning to be understood. But what happens to the dopaminergic neurons that remain? How do they respond to falling levels of dopamine? The prevailing view is that dopamine release and the activity of dopaminergic neurons is controlled by homeostatic mechanisms (3). That is, activity is regulated to maintain an optimal basal level of dopamine in target structures by feedback mechanisms that sense dopamine. The work by Robinson et al. (4) in this issue of PNAS challenges the completeness of this view. The authors show that dopaminergic neurons that do not release dopamine exhibit normal activity patterns in awake, behaving mice. This finding suggests that, although dopamine may be important, other signaling factors must control the activity patterns of dopaminergic neurons. The existence of other homeostatic signals has fundamental implications not only for our understanding of the compensations in earlystage PD but also for mechanisms contributing to other dopaminergic disorders like attention deficit hyperactivity disorder and drug abuse. A major figure in the story told by Robinson et al. (4) is the experimental subject. Previous studies focusing longterm adaptations to dopamine depletion have relied on chemical toxins like 6hydroxydopamine or 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (1). Although both agents lower brain dopamine levels effectively, they do so by poisoning dopaminergic neurons, making subsequent study of them problematic. These models also suffer from the inability to distinguish between compensations that are induced by the depletion of dopamine and those that are triggered by the loss of dopaminergic neurons. This distinction is crucial, particularly when thinking about therapeutic strategies in disorders like PD, because ‘‘dopaminergic’’ neurons may be releasing neurotransmitters or neurotrophic factors other than dopamine that are important to the proper functioning of target tissues. To overcome this limitation, Richard Palmiter’s group (5) engineered a mouse in which