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Abstract
SUMMARYCharacterizing dopaminergic neuronal development and function in novel genetic animal models might uncover strategies for researchers to develop disease-modifying treatments for neurologic disorders. Id2 is a transcription factor expressed in the developing central nervous system. Id2−/− mice have fewer dopaminergic neurons in the olfactory bulb and reduced olfactory discrimination, a pre-clinical marker of Parkinson’s disease. Here, we summarize behavioral, histological and in vitro molecular biological analyses to determine whether midbrain dopaminergic neurons are affected by Id2 loss. Id2−/− mice were hyperactive at 1 and 3 months of age, but by 6 months showed reduced activity. Id2−/− mice showed age-dependent histological alterations in dopaminergic neurons of the substantia nigra pars compacta (SNpC) associated with changes in locomotor activity. Reduced dopamine transporter (DAT) expression was observed at early ages in Id2−/− mice and DAT expression was dependent on Id2 expression in an in vitro dopaminergic differentiation model. Evidence of neurodegeneration, including activated caspase-3 and glial infiltration, were noted in the SNpC of older Id2−/− mice. These findings document a novel role for Id2 in the maintenance of midbrain dopamine neurons. The Id2−/− mouse should provide unique opportunities to study the progression of neurodegenerative disorders involving the dopamine system.
Highlights
Dopamine (DA) is a catecholaminergic neurotransmitter of the central nervous system (CNS) that plays a prominent role in cognition as well as motor and endocrine function (Iversen and Iversen, 2007)
They report age-dependent degeneration of midbrain DA tissues in these mice. They show that histological abnormalities that arise in Id2–/– mice occur in association with reduced activity, following a period of early life hyperactivity
By contrast, when tested at 6 months of age, the same Id2−/− mice did not have a significantly increased locomotor activity compared with wild-type mice and had significantly reduced rotational activity compared with measures at 3 months of age (Fig. 1A-C), suggesting that these changes were age-dependent
Summary
Dopamine (DA) is a catecholaminergic neurotransmitter of the central nervous system (CNS) that plays a prominent role in cognition as well as motor and endocrine function (Iversen and Iversen, 2007). Agedependent neurodegeneration of midbrain dopaminergic (mDA) neurons of the SNpC underlies altered motor function in patients with Parkinson’s disease (PD) (Dauer and Przedborski, 2003). Dysfunction of mDA neurons is a prominent characteristic of neuropsychiatric and addictive disorders (Chao and Nestler, 2004). Understanding the molecular pathways mediating the development and survival of mDA neurons and how perturbations of these pathways affect mature DA neurons should provide insights into the prevention and treatment of these disorders. The induction, specification and maturation of mDA neurons can be monitored by evaluation of the temporal pattern of expression of genes associated with differentiation of DA neurons. Expression of DAT and establishment of DA re-uptake are among the last events in the maturation of mDA neurons, and indicative of terminal differentiation
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