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Abstract :
[en] Dopamine Transporter Deficiency Syndrome (DTDS), also known as infantile parkinsonism-dystonia, is a rare and hereditary disease in which the functioning of Dopamine Transporter (DAT) protein is impaired. At the early stage of the pathology, patients show hyperkinesia that progressively evolve into motor deficits and stereotypical movements. To better study the behavioral, functional, and molecular mechanisms that underlie this pathology, we took advantage of DAT knockout (DAT KO) rats, an animal model which shows all the major clinical features of DTDS. One of the critical components in DA actions is the reciprocal modulation with the glutamate transmission. To obtain a clear picture of the cellular mechanisms involved in these interactions, we decided to deepen our knowledge about the effect of the DAT deletion on the homeostasis of the glutamate synapse.
Behaviorally, we found that DAT deletion determine hyperactivity behaviors in rats exposed to the open field test, DAT KO rats show indeed a significant increase in velocity and in distance travelled. A functional explanation for this hyperactivity can be seen when measuring the electrophysiological activity in the ventral part of the striatum. Using theta-burst stimulation (TBS) protocol, we were able to induce a long-lasting long-term depotentiation (LTD) in wild-type animals, while LTD was critically impaired in DAT KO rats. Moreover, these changes were accompanied by alterations in the expression of the main glutamatergic determinants. We observed a reduced expression of the main subunits of NMDA receptors as well as of their specific scaffolding proteins in the post-synaptic density of the striatum, paralleled with an increased trafficking of the same determinants toward the extra-synaptic sites.
In conclusion, our data show that increased levels of DA have rearranged the glutamatergic synapse in the striatum leading to a destabilization and depotentiation of the glutamatergic neurotransmission.
