A sensitizing d-amphetamine dose regimen induces long-lasting spinophilin and VGLUT1 protein upregulation in the rat diencephalon

Boikess, Steven R.; O’Dell, Steven J.; Marshall, John F.

doi:10.1016/j.neulet.2009.11.042

Cited by 10 publications

(9 citation statements)

References 43 publications

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“…Using HA immunoprecipitation from different cell types and TMT labeling, we probed the spinophilin interactome in the striatum of saline compared to amphetamine treated animals. As previously observed in rats [58,59], the amount of spinophilin detected (based on labeled peptide abundance) was increased following amphetamine treatment. Interestingly, across all samples the abundance of the different proteins was greater in the amphetamine-treated compared to the control treated lysates, even when normalizing to the increased spinophilin expression.…”

Section: Discussionsupporting

confidence: 77%

“…Changes in MSN dendritic spine density and morphology, perturbations in synaptic transmission and concomitant aberrant dopaminergic signaling are all major contributors to striatal disease states like drug addiction and myriad others [23,26,27,31,57]. In addition, psychostimulant administration, which drives hyper-dopaminergic responses was shown to increase spinophilin expression in the striatum [58,59]. As stated above, alterations in DA levels will regulate DA receptor activity and downstream activation of kinases, such as PKA.…”

Section: Introductionmentioning

confidence: 99%

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Proteomic Analysis of the Spinophilin Interactome in Rodent Striatum Following Psychostimulant Sensitization

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Proteomic Analysis of the Spinophilin Interactome in Rodent Striatum Following Psychostimulant Sensitization

et al. 2018

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“…However, little is known, about the cellular and molecular mechanisms of the effects of psychostimulant drugs in the hippocampus. In the few studies performed in rodents, psychostimulant-induced structural plasticity in non-reward regions like the hippocampus, has been studied using long chronic administration regimens (Rademacher et al, 2006 ; Shen et al, 2006 ; Boikess et al, 2010 ; Ahn et al, 2013 ). Here, we show for the first time that amphetamine administrated in a two-injection protocol increases dendritic spine density in CA1 pyramidal neurons of thy1-GFP transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Cdk5 Is Essential for Amphetamine to Increase Dendritic Spine Density in Hippocampal Pyramidal Neurons

Ferreras

Fernández

Danelon

et al. 2017

Front. Cell. Neurosci.

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Psychostimulant drugs of abuse increase dendritic spine density in reward centers of the brain. However, little is known about their effects in the hippocampus, where activity-dependent changes in the density of dendritic spine are associated with learning and memory. Recent reports suggest that Cdk5 plays an important role in drug addiction, but its role in psychostimulant’s effects on dendritic spines in hippocampus remain unknown. We used in vivo and in vitro approaches to demonstrate that amphetamine increases dendritic spine density in pyramidal neurons of the hippocampus. Primary cultures and organotypic slice cultures were used for cellular, molecular, pharmacological and biochemical analyses of the role of Cdk5/p25 in amphetamine-induced dendritic spine formation. Amphetamine (two-injection protocol) increased dendritic spine density in hippocampal neurons of thy1-green fluorescent protein (GFP) mice, as well as in hippocampal cultured neurons and organotypic slice cultures. Either genetic or pharmacological inhibition of Cdk5 activity prevented the amphetamine–induced increase in dendritic spine density. Amphetamine also increased spine density in neurons overexpressing the strong Cdk5 activator p25. Finally, inhibition of calpain, the protease necessary for the conversion of p35 to p25, prevented amphetamine’s effect on dendritic spine density. We demonstrate, for the first time, that amphetamine increases the density of dendritic spine in hippocampal pyramidal neurons in vivo and in vitro. Moreover, we show that the Cdk5/p25 signaling and calpain activity are both necessary for the effect of amphetamine on dendritic spine density. The identification of molecular mechanisms underlying psychostimulant effects provides novel and promising therapeutic approaches for the treatment of drug addiction.

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“…An absence of a change in synaptophysin expression in the habenula has been observed in response to another stressor. For instance, increases in expression levels of vesicular glutamate transporter and spinophilin in the medial habenula, as well as in other structures, were observed following sensitization with D-amphetamine while synaptophysin expression remained unchanged [26]. …”

Section: Discussionmentioning

confidence: 99%

The habenula and iron metabolism in cerebral mouse models of multiple sclerosis

Sands

Tsau

Levine

2015

Neuroscience Letters

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Iron accumulates in the CNS of patients with multiple sclerosis, but our understanding of the mechanism accounting for this accumulation is unclear. Mouse models of cerebral experimental autoimmune encephalomyelitis (EAE) in C57BL/6 and SJL mice were used together with a histochemical stain for iron and immunohistochemical stains for transferrin receptor, synaptophysin, iron regulatory protein 1 (IRP1) and/or IRP2 to investigate the role of disease activity on CNS iron metabolism. The expression of transferrin receptor, but not IRP1 or IRP2, increased in the medial habenula, which is adjacent to the third ventricle, in response to both types of cerebral EAE. In the habenula, the elevated expression of transferrin receptor in C57BL/6 mice with cerebral EAE was generally restricted to the medial habenula while the expression in SJL mice with cerebral EAE was more diffusely expressed. Iron levels were increased in all regions of the habenula in C57BL/6 mice with cerebral EAE, and in the medial and medial lateral but not the lateral habenula in SJL mice with cerebral EAE. Synaptophysin, which has been observed previously in endocytic vesicles together with the transferrin receptor, was concentrated at the medial habenula, but its levels did not increase with disease in C57BL/6 mice with cerebral EAE. Our results support the model that the medial habenula responds to disease activity by upregulating transferrin receptor to facilitate the movement of iron into the brain from the third ventricle, raising the possibility that a similar mechanism accounts for iron accumulation in deep gray matter structures in patients with multiple sclerosis.

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A sensitizing d-amphetamine dose regimen induces long-lasting spinophilin and VGLUT1 protein upregulation in the rat diencephalon

Cited by 10 publications

References 43 publications

Proteomic Analysis of the Spinophilin Interactome in Rodent Striatum Following Psychostimulant Sensitization

Proteomic Analysis of the Spinophilin Interactome in Rodent Striatum Following Psychostimulant Sensitization

Cdk5 Is Essential for Amphetamine to Increase Dendritic Spine Density in Hippocampal Pyramidal Neurons

The habenula and iron metabolism in cerebral mouse models of multiple sclerosis

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