Shared Motivational Functions of Ventral Striatum D1 and D2 Medium Spiny Neurons

Flanigan, Meghan E.; LeClair, Katherine B.

doi:10.1523/jneurosci.0882-17.2017

Cited by 18 publications

(14 citation statements)

References 12 publications

(5 reference statements)

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“…However, a common alteration in these pathologies is revealed by functional imaging studies that have consistently described abnormal reward-related activity of dopaminoceptive regions of the reward system, including the striatum, in patients with MDD (Bress et al, 2013;Pizzagalli et al, 2009), BP (Caseras et al, 2013;Mason et al, 2014), and SCZ (Howes et al, 2009;Morris et al, 2012). Strikingly, similar to what has been described in psychiatric disorders, in n-3 PUFA-deficient animals, we found no obvious difference in markers of dopamine transmission but rather an alteration in the functionality of dopaminoceptive MSN network in the NAc, which has been largely shown to be involved in the modulation of motivation (Carvalho Poyraz et al, 2016;Flanigan and LeClair, 2017;Gallo et al, 2018;Natsubori et al, 2017;Soares-Cunha et al, 2016;Trifilieff et al, 2013).…”

Section: Discussionsupporting

confidence: 80%

Causal Link between n-3 Polyunsaturated Fatty Acid Deficiency and Motivation Deficits

et al. 2020

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Section: Discussionsupporting

confidence: 80%

Causal Link between n-3 Polyunsaturated Fatty Acid Deficiency and Motivation Deficits

et al. 2020

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“…To determine if these proteins interact with spinophilin in a specific manner, we dissected out total (dorsal and ventral (e.g., accumbens)) striatum (Str) and olfactory tubercle (OT), a further ventral portion of the striatum from wildtype and whole-body spinophilin KO animals. We chose these regions based on their roles in psychostimulant sensitization [31,32,33]. We immunoprecipitated striatal and tubercle lysates with a spinophilin antibody and immunoblotted for spinophilin, SAP102, Srcin1, and clathrin heavy chain.…”

Section: Resultsmentioning

confidence: 99%

“…The dStr is innervated by dopaminergic projections arising from the substantia nigra (SN) and has been functionally described as a modulator of motor domains specifically involving action selection and initiation [29,30]. The vStr is innervated by dopaminergic projections from the ventral tegmental area (VTA) and is involved in mediating reward and motivational domains [31,32,33]. However, studies also suggest that there is significant overlap in motor and reward functional domains within the striatum [34,35].…”

Section: Introductionmentioning

confidence: 99%

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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“…We also observe a similar signature for genes where nominal significance has been observed for clustered DNMs. While many of the genes enriched for D1+ and D2+ expression are not exclusive to the striatum and are more broadly expressed (as demonstrated by the enrichment signal at the lowest specificity threshold), the striatum has been implicated in ID and autism pathology by numerous studies [97][98][99][100][101][102][103][104][105][106] . The striatum is particularly compelling as it has been linked to repetitive behaviors 97 core to the autism phenotype and also to genes known to be involved in DD, including CHD8, SHANK3, FOXP2, and KCNA4 98,99,102,105,106 .…”

Section: Discussionmentioning

confidence: 99%

Neurodevelopmental disease genes implicated byde novomutation and CNV morbidity

Coe

Stessman²,

Sulovari

et al. 2017

Preprint

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We combined de novo mutation (DNM) data from 10,927 cases of developmental delay and autism to identify 301 candidate neurodevelopmental disease genes showing an excess of missense and/or likely gene-disruptive (LGD) mutations. 164 genes were predicted by two different DNM models, including 116 genes with an excess of LGD mutations. Among the 301 genes, 76% show DNM in both autism and intellectual disability/developmental delay cohorts where they occur in 10.3% and 28.4% of the cases, respectively. Intersecting these results with copy number variation (CNV) morbidity data identifies a significant enrichment for the intersection of our gene set and genomic disorder regions (36/301, LR+ 2.53, p=0.0005). This analysis confirms many recurrent LGD genes and CNV deletion syndromes (e.g., KANSL1, PAFAH1B1, RA1, etc.), consistent with a model of haploinsufficiency. We also identify genes with an excess of missense DNMs overlapping deletion syndromes (e.g., KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Finally, we also identify pathogenic CNVs overlapping more than one recurrently mutated gene (e.g., Sotos and Kleefstra syndromes) raising the possibility that multiple gene-dosage imbalances may contribute to phenotypic complexity of these disorders. Network analyses of genes showing an excess of DNMs confirm previous well-known enrichments but also highlight new functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum for both recurrently mutated genes and genes where missense mutations cluster.

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Shared Motivational Functions of Ventral Striatum D1 and D2 Medium Spiny Neurons

Cited by 18 publications

References 12 publications

Causal Link between n-3 Polyunsaturated Fatty Acid Deficiency and Motivation Deficits

Causal Link between n-3 Polyunsaturated Fatty Acid Deficiency and Motivation Deficits

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

Neurodevelopmental disease genes implicated byde novomutation and CNV morbidity

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