Indiana University-Purdue University Indianapolis (IUPUI) / Striatal-mediated pathological disease-states such as Obsessive-Compulsive
Disorder (OCD), Parkinson’s Disease (PD), and psychostimulant drug addiction/abuse
are coupled with distinct motor movement abnormalities. In addition, these disorders are
associated with perturbed synaptic transmission. Proper synaptic transmission is critical
for maintaining neuronal communication. Furthermore, in many striatal-dependent
disease-states, the principle striatal neurons, medium spiny neurons (MSNs), exhibit
differential perturbations in downstream signaling. Signal transduction pathways that are
localized to the glutamatergic post-synaptic density (PSD) of GABAergic MSNs regulate
protein phosphorylation in a tightly controlled manner. Alterations in the control of this
phosphorylation in striatal MSNs are observed in myriad striatal pathological diseasestates
and can give rise to perturbations in synaptic transmission. While serine/threonine
kinases obtain substrate specificity, in part, by phosphorylating specific consensus sites,
serine/threonine phosphatases such as protein phosphatase 1 (PP1) are much more
promiscuous. To obtain substrate selectivity, PP1 associates with targeting proteins. The
major targeting protein for PP1 in the PSD of striatal dendritic spines is spinophilin.
Spinophilin not only binds PP1, but also concurrently interacts with myriad synaptic
proteins. Interestingly, dopamine depletion, an animal model of PD, modulates
spinophilin protein-protein interactions in the striatum. However, spinophilin function on basal striatal-mediated motor behaviors such as the rotarod or under hyperdopaminergic
states such as those observed following psychostimulant-induced behavioral sensitization
are less well characterized. To elucidate spinophilin function more specifically, we have
generated multiple transgenic animals that allow for cell type-specific loss of spinophilin
as well as cell-specific interrogation of spinophilin protein interactions. Here, I report the
functional role of spinophilin in regulating striatal mediated motor behaviors and
functional changes associated with amphetamine-induced locomotor sensitization. In
addition, we define changes in spinophilin protein-protein interactions that may mediate
these behavioral changes. Furthermore, global loss of spinophilin abrogates
amphetamine-induced sensitization and plays a critical role in striatal motor learning and
performance. The data suggest that the striatal spinophilin protein interactome is
upregulated in MSNs following psychostimulant administration. In addition, loss of
spinophilin changes protein expression in myriad psychostimulant-mediated striatal
adaptations. Taken together the data suggests that spinophilin’s protein-protein
interactions in the striatum are obligate for appropriate striatal mediated motor function.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/29735 |
| Date | 07 1900 |
| Creators | Watkins, Darryl Shumon |
| Contributors | Yamamoto, Bryan K., Atwood, Brady K., Baucum, Anthony J. II, Hudmon, Andy, Logrip, Marian L. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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