Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility

Kosillo, Polina; Doig, Natalie M.; Ahmed, Kamran M.; Agopyan-Miu, Alexander H.C.W.; Wong, Corinna D.; Conyers, Lisa; Threlfell, Sarah; Magill, Peter J.; Bateup, Helen S.

doi:10.1038/s41467-019-13396-8

Cited by 49 publications

(82 citation statements)

References 80 publications

(108 reference statements)

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“…Loss of Tsc1 caused a gene dose-sensitive increase in p-S6 levels in both dSPNs and iSPNs, indicating mTORC1 pathway hyperactivity in both cell types . Prior studies have demonstrated pronounced somatic hypertrophy in Tsc1 KO neurons in various brain regions, consistent with the known role of mTORC1 in regulating cell size (Bateup et al, 2011;Feliciano et al, 2011;Kosillo et al, 2019;Malik et al, 2019;Normand et al, 2013;Tsai et al, 2012). In the striatum, we observed a relatively modest but significant increase in the soma volume of dSPN-Tsc1 KO and iSPN-Tsc1 KO neurons (Fig.…”

Section: Upregulation Of Mtorc1 and Somatic Hypertrophy In Spns With supporting

confidence: 89%

“…Intrinsic hypoexcitability has been observed in other neuron types with Tsc1 loss (Bateup et al, 2013;Kosillo et al, 2019;Normand et al, 2013;Tsai et al, 2012;Yang et al, 2012), and likely results from somatic hypertrophy (see Fig. 1), as membrane area and excitability are inversely related.…”

Section: Loss Of Tsc1 Increases Cortical Drive Of Direct Pathway Strimentioning

confidence: 78%

“…Increased cortico-dSPN excitability results from enhanced synaptic transmission Enhanced responses in dSPN-Tsc1 Het and KO mice to cortical terminal stimulation could result from increased intrinsic membrane excitability, increased synaptic excitation, or both. Indeed, Tsc1 deletion has diverse effects on intrinsic and synaptic excitability depending on the cell type studied (Bateup et al, 2013;Benthall et al, 2018;Ehninger et al, 2008;Kosillo et al, 2019;Malik et al, 2019;Normand et al, 2013;Tavazoie et al, 2005;Tsai et al, 2012;Yang et al, 2012). To test if changes in intrinsic excitability occurred in dSPN-Tsc1 KO neurons, we injected positive current and measured the number of APs fired as a function of current step amplitude.…”

Section: Loss Of Tsc1 Increases Cortical Drive Of Direct Pathway Strimentioning

confidence: 99%

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Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Benthall

Cording

Chen

et al. 2019

Preprint

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Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder in which individualsfrequently present with autism spectrum disorder (ASD). A core diagnostic criterion for ASD is the presence of restricted, repetitive behaviors (RRBs), which may result from abnormal activity in striatal circuits that mediate motor learning, action selection and habit formation. Striatal control over motor behavior relies on the coordinated activity of two subtypes of principle neurons, direct pathway and indirect pathway spiny projection neurons (dSPNs or iSPNs, respectively), which provide the main output of the striatum. To test if altered striatal activity is sufficient to cause repetitive behaviors in the context of TSC, we conditionally deleted Tsc1 from dSPNs or iSPNs in mice and measured the consequences on synaptic function and motor behavior. We find that mice with loss of Tsc1 from dSPNs, but not iSPNs, have enhanced motor routine learning in the accelerating rotarod task. This increased motor learning is associated with an impairment in endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses in the dorsal striatum. Consistent with a loss of eCB-LTD, disruption of Tsc1 in dSPNs, but not iSPNs, results in a strong enhancement of corticostriatal synaptic drive. Together these findings demonstrate that within the striatum dSPNs show selective sensitivity to Tsc1 loss and indicate that enhanced activation of the striatal direct pathway is a potential contributor to RRBs in TSC.

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Section: Upregulation Of Mtorc1 and Somatic Hypertrophy In Spns With supporting

confidence: 89%

Section: Loss Of Tsc1 Increases Cortical Drive Of Direct Pathway Strimentioning

confidence: 78%

Section: Loss Of Tsc1 Increases Cortical Drive Of Direct Pathway Strimentioning

confidence: 99%

See 1 more Smart Citation

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Benthall

Cording

Chen

et al. 2019

Preprint

Self Cite

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“…Recently, we proposed that the TOR metabolic signaling network evolves through exaptation by coopting existing pathways to serve new functions relevant to specific lineages ( Brunkard, 2020 ). For example, TOR gained new functions when eukaryotic lineages evolved multicellularity, such as coordinating plasmodesmatal (intercellular) transport in plants ( Brunkard et al, 2020 ) or regulating cellular differentiation and cell type-specific metabolisms in humans ( Brunkard, 2020 ; Kosillo et al, 2019 ), as examples. Similarly, here, we provide evidence that plants exapted the TOR-LARP1-5′TOP signaling axis to regulate translation of proteins involved in developmental patterning and auxin signaling ( Figure 5G ), pathways that did not exist in the unicellular ancestor of plants and animals that first evolved TOR-LARP1-5′TOP signaling.…”

Section: Discussionmentioning

confidence: 99%

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation

Scarpin

Leiboff

Brunkard

2020

eLife

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TARGET OF RAPAMYCIN (TOR) is a protein kinase that coordinates eukaryotic metabolism. In mammals, TOR specifically promotes translation of ribosomal protein mRNAs when amino acids are available to support protein synthesis. The mechanisms controlling translation downstream from TOR remain contested, however, and are largely unexplored in plants. To define these mechanisms in plants, we globally profiled the plant TOR-regulated transcriptome, translatome, proteome, and phosphoproteome. We found that TOR regulates ribosome biogenesis in plants at multiple levels, but through mechanisms that do not directly depend on 5′ oligopyrimidine tract motifs (5′TOPs) found in mammalian ribosomal protein mRNAs. We then show that the TOR-LARP1-5′TOP signaling axis is conserved in plants and regulates expression of a core set of eukaryotic 5′TOP mRNAs, as well as new, plant-specific 5′TOP mRNAs. Our study illuminates ancestral roles of the TOR-LARP1-5′TOP metabolic regulatory network and provides evolutionary context for ongoing debates about the molecular function of LARP1.

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“…in CINs with FS properties, with no apparent changes to passive membrane properties. This result differs from the deletion of TSC1 in mice, which have several alterations in both passive and active membrane properties (Normand et al, 2013;Kosillo et al, 2019;Malik et al, 2019). AHPs play an essential role in shaping neuronal firing properties (Hille, 2001).…”

Section: Discussionmentioning

confidence: 96%

A Human TSC1 Variant Screening Platform in Gabaergic Cortical Interneurons for Genotype to Phenotype Assessments

Wundrach

Martinetti

Stafford

et al. 2020

Front. Mol. Neurosci.

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The TSC1 and TSC2 genes are connected to multiple syndromes from Tuberous Sclerosis Complex (TSC) to autism spectrum disorder (ASD), with uncertainty if genetic variants cause all or subsets of phenotypes based on the location and type of change. For TSC1, few have addressed if non-TSC associated genetic variants have direct contributions to changes in neurological genotype-to-phenotype impacts, including elevated rates of ASD and seizures. Dominant variants cause TSC, yet TSC1 has many heritable variants not dominant for TSC that are poorly understood in neurological function, with some associated with ASD. Herein, we examined how missense variants in TSC1, R336W, T360N, T393I, S403L, and H732Y, impacted the development of cortical inhibitory interneurons, cell-types whose molecular, cellular, and physiological properties are altered after the loss of mouse TSC1. We found these variants complemented a known phenotype caused by loss of TSC1, increased cell size. However, distinct variants, particularly S403L showed deficits in complementing an increase in parvalbumin levels and exhibited smaller amplitude after hyperpolarizations. Overall, these data show that subtle phenotypes can be induced by some TSC1 missense variants and provide an in vivo system to assess TSC1 variants' neurological impact better.

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Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility

Cited by 49 publications

References 80 publications

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation

A Human TSC1 Variant Screening Platform in Gabaergic Cortical Interneurons for Genotype to Phenotype Assessments

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