Objective/Rationale:
The loss of striatal dopamine that accompanies Parkinson’s disease disrupts the function of the neurotransmitter glutamate within this same region. Glutamate transmission involves many different kinds of receptors. Of particular note, the NMDA class of glutamate receptors plays a key role in inducing long-term changes in how these synapses work. A specific subunit of the NMDA receptor, NR2B, has been proposed to play a particularly important role in these NMDA receptor functions.
Project Description:
To test the role of the NR2B subunit in the motor deficits produced by the loss of striatal dopamine, as well as in the dyskinesias produced by repeated levodopa administration, we will use a novel genetically modified pre-clinical model in which the NR2B gene can be deleted in specific populations of neurons, including striatal neurons. We will use these NR2B “knockout” mice along with littermates that retain NR2B to explore the effects of neurotoxin-induced striatal dopamine depletion on motor function. In addition, we will explore the effects of NR2B knockout on motor responses to repeated levodopa administration.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
These studies have the potential to provide a non-dopamine drug target for development in the treatment both of the progression of Parkinson’s Disease and in the moderation of dyskinesias associated with long-term levodopa administration.
Anticipated Outcome:
We predict that the “knockout” of NR2B will dampen the dyskinetic-like motor responses of dopamine-depleted mice treated with levodopa. We may also observe a reduced disruption of motor function by the dopamine depletion in the knockout mice.