Behavioral abnormalities and Parkinson's-like histological changes resulting from Id2 inactivation in mice

Characterizing 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.