Upregulation and axonal transport of synaptotagmin- IV in the direct-pathway medium spiny neurons in hemi-parkinsonian rats induced by dopamine D1 receptor stimulation.

Synaptotagmin- IV (Syt- IV) may function as a regulator of Ca²⁺-dependent synaptic transmission. In the hemi-parkinsonian rats with unilateral lesions of dopaminergic nigrostriatal neurons Syt- IV and substance-P ( SP) mRNAs could be upregulated within the dopaminergically hypersensitive striatum of the lesioned brain hemisphere via the stimulation of striatal dopamine D1 (D1-R), but not D2 receptors. The hypersensitive D1-R-mediated transmission may be the culprit for the undesired expression of levodopa-induced dyskinesia, implying the involvement of Syt- IV and SP in the process. First, striatal cellular phenotypes expressing Syt- IV were determined. It was found to be expressed in all striatal neurons and a small population of astrocytes. Then it was examined, if the D1-R-mediated upregulation of Syt- IV mRNA may result in the upregulation of the translated protein. It was found that, after acute stimulation with a selective D1 agonist, (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide ( SKF-82958), Syt- IV was elevated within the SP-expressing striatal neurons of the lesioned side. This was followed by the upregulation of Syt- IV, but not of its mRNA, within the ipsilateral target nuclei of the direct-pathway medium spiny neurons, indicating axonal transport of de novo synthesized protein to their SP-positive synaptic terminals. However, despite the striatal upregulation of SP and Syt- IV following a similar time-course, their subcellular co-localization within the axonal terminals was not found. It was therefore suggested that Syt- IV may regulate the hypersensitive striatal synaptic transmission, although via a SP-independent mechanism. [ABSTRACT FROM AUTHOR]