The brain is made up of many different types of neurons. For example, one class of neuron in the striatum is called the medium spiny neuron (MSN). These spiny neurons are so called because they contain dendritic spines that form connections, called synapses, with glutamate-containing axons from the cortex and dopamine containing axons from the substantia nigra. The dendritic spines on the MSNs contain signaling and scaffolding molecules in an electron dense area called the postsynaptic density. Psychostimulant drugs of abuse act to increase dopamine release from nigral dopaminergic neurons, which has downstream effects on proteins that are localized to MSN dendritic spines. One protein, spinophilin, is increased upon chronic exposure to psychostimulant drugs of abuse. Spinophilin is the most abundant protein phosphatase 1 (PP1) targeting protein localized to an area of dendritic spines called the postsynaptic density. Moreover, spinophilin- dependent targeting of PP1 is important in modulating normal synaptic physiology and function. Striatal MSNs can be subdivided into two classes, direct (dMSNs) and indirect (iMSNs) pathway neurons. There are very few ways to evaluate the function of synaptic proteins such as spinophilin in the two MSN classes. This is important because the two classes of MSNs have different responses to psychostimulant exposure. The goal of our proposal is to determine the function of spinophilin in the two classes of MSNs in regulating responses to sensitizing regimens of psychomotor stimulants such as cocaine and amphetamine. These regimens induce specific neuronal changes that are indicative of addiction in humans. Determining the cell-specific role of spinophilin in mediating pathologies associated with these drugs of abuse will identify new pathways that can be targeted for treatment of addiction or other pathologies associated with alterations in dopamine signaling, such as Parkinson disease or obsessive-compulsive disorder. In this proposal, we hypothesize that spinophilin plays a unique role in the two MSN populations in mediating psychostimulant- induced pathologies. This hypothesis will be tested using the following specific aims:
Aim 1. Delineate the regulation of spinophilin interactions in dMSNs and iMSNs following psychostimulant sensitization. In this aim, we will see how psychostimulants alter spinophilin interactions in dMSNs and iMSNs.
Aim 2. Determine the role of spinophilin in dMSNs and iMSNs on modulating psychostimulant sensitization-dependent changes in MSN physiology and structure. In this aim we will determine how loss of spinophilin in dMSNs or iMSNs of adult animals alters synaptic physiology and dendritic spine number.
Aim 3. Determine the role of spinophilin in dMSNs and iMSNs on modulating behavioral changes induced by psychostimulant drugs of abuse. In this aim we will determine how loss of spinophilin in dMSNs or iMSNs alters behavioral changes observed in response to psychostimulant administration.
Molecular changes that occur in the humans exposed to psychostimulants such as amphetamines are not fully known. Spinophilin is a brain protein that regulates responses to drugs of abuse via interactions with myriad synaptic proteins. This project will determine the role of spinophilin in specific cell types, in order to identify novel pathways that can be targeted to help ameliorate pathologies associated with psychostimulant addiction.
| Morris, Cameron W; Watkins, Darryl S; Salek, Asma B et al. (2018) The association of spinophilin with disks large-associated protein 3 (SAPAP3) is regulated by metabotropic glutamate receptor (mGluR) 5. Mol Cell Neurosci 90:60-69 |
