Abstract
Glutamatergic projections from the cortex and dopaminergic projections from the substantia nigra or ventral tegmental area synapse on dendritic spines of specific GABAergic medium spiny neurons (MSNs) in the striatum. Direct pathway MSNs (dMSNs) are positively coupled to protein kinase A (PKA) signaling and activation of these neurons enhance specific motor programs whereas indirect pathway MSNs (iMSNs) are negatively coupled to PKA and inhibit competing motor programs. An imbalance in the activity of these two programs is observed following increased dopamine signaling associated with exposure to psychostimulant drugs of abuse. Alterations in MSN signaling are mediated by changes in MSN protein post-translational modifications, including phosphorylation. Whereas direct changes in specific kinases, such as PKA, regulate different effects observed in the two MSN populations, alterations in the specific activity of serine/threonine phosphatases, such as protein phosphatase 1 (PP1) are less well known. This lack of knowledge is due, in part, to unknown, cell-specific changes in PP1 targeting proteins. Spinophilin is the major PP1-targeting protein in striatal postsynaptic densities. Using proteomics and immunoblotting approaches along with a novel transgenic mouse expressing hemagglutainin (HA)-tagged spinophilin in dMSNs and iMSNs, we have uncovered cell-specific regulation of the spinophilin interactome following a sensitizing regimen of amphetamine. These data suggest regulation of spinophilin interactions in specific MSN cell types and may give novel insight into putative cell-specific, phosphatase-dependent signaling pathways associated with psychostimulants.
Highlights
Psychostimulant drug abuse is becoming increasingly popular and costly globally [1,2].Psychostimulant drugs of abuse, such as methamphetamine, amphetamine, and cocaine, have been associated with dopamine (DA) receptor dysfunction, improper synaptic transmission, and other neuronal perturbations that may contribute to addiction pathology [3,4,5,6,7,8]
We found that there was a greater association of spinophilin with multiple proteins 72 h following amphetamine treatment and that this occurred in both Cre-driver lines
While our preliminary study suggests the level of increase was greater overall in the Direct pathway MSNs (dMSNs) compared to the indirect pathway MSNs (iMSNs), it is unclear if these changes will persist in both populations and future studies will need to evaluate the persistence of these changes and the link between spinophilin and modulation of dendritic spine density
Summary
Psychostimulant drugs of abuse, such as methamphetamine, amphetamine, and cocaine, have been associated with dopamine (DA) receptor dysfunction, improper synaptic transmission, and other neuronal perturbations that may contribute to addiction pathology [3,4,5,6,7,8]. DA plays a critical role in basal ganglia regulated motor programs [17,18,19,20,21,22]. The striatum is the largest structure within the basal ganglia and has been shown to play a role in disease states, such as Huntington and Parkinson Disease (HD and PD, respectively), and neurological disorders like obsessive-compulsive disorder (OCD) and drug addiction/abuse [23,24,25,26,27,28]. The dStr is innervated by dopaminergic projections arising from the substantia nigra (SN) and has been functionally described as a modulator of motor domains involving action selection and initiation [29,30]
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