Reduced Juvenile Long-Term Depression in Tuberous Sclerosis Complex Is Mitigated in Adults by Compensatory Recruitment of mGluR5 and Erk Signaling

Potter, Wyatt B.; Basu, Trina; O’Riordan, Kenneth J.; Kirchner, Allison; Rutecki, Paul; Bürger, Corinna; Roopra, Avtar

doi:10.1371/journal.pbio.1001627

Cited by 43 publications

(53 citation statements)

References 50 publications

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“…Our findings are consistent with prior reports showing that brain-wide heterozygous deletion of Tsc2 or disruption of the translational regulator eIF4E, which increases protein synthesis, impair reversal but not acquisition learning in water maze tasks (Potter et al, 2013;Santini et al, 2013). Our work suggests that these types of impairments may be attributable to dopaminergic dysfunction, consistent with the involvement of DA in cognitive flexibility in rodents and humans (Darvas and Palmiter, 2011;Klanker et al, 2013).…”

Section: Behavioral Consequences Of Mtor-related Dopaminergic Dysfuncsupporting

confidence: 93%

Tsc1-mTOR signaling controls the structure and function of midbrain dopamine neurons

Kosillo¹,

Doig

Ahmed³

et al. 2018

Preprint

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mTOR complex 1 (mTORC1) is a central coordinator of cell growth and metabolism. Mutations in regulators of mTORC1 cause syndromic disorders with a high prevalence of cognitive and psychiatric conditions. To elucidate the cellular origins of these manifestations, we conditionally deleted the gene encoding the mTORC1 negative regulator Tsc1 from mouse midbrain dopamine neurons, which modulate motor, affective, and cognitive behaviors that are frequently affected in psychiatric disorders. Loss of Tsc1 and constitutive activation of mTORC1 strongly impacted the properties of dopamine neurons, causing somatodendritic hypertrophy, reduced intrinsic excitability, altered axon terminal ultrastructure, and severely impaired dopamine release. These perturbations were associated with selective deficits in cognitive flexibility, which could be prevented by genetic reduction of the obligatory mTORC1 protein Raptor. Our results establish a critical role for mTORC1 in setting the functional properties of midbrain dopamine neurons, and indicate that dopaminergic dysfunction may underlie cognitive inflexibility in mTOR-related syndromes.

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Section: Behavioral Consequences Of Mtor-related Dopaminergic Dysfuncsupporting

confidence: 93%

Tsc1-mTOR signaling controls the structure and function of midbrain dopamine neurons

Kosillo¹,

Doig

Ahmed³

et al. 2018

Preprint

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“…Given the current schema, we expected rapamycin to fully inhibit mGluR-LTD following ELS as well as in controls, as previously shown (Hou and Klann, 2004; Potter et al, 2013; Sharma et al, 2010), as mTOR is responsible for activating protein synthesis (Sharma et al, 2010) and also for limiting protein synthesis (Tang et al, 2002). Our results in ELS rats were contrary to what was expected.…”

Section: Discussionmentioning

confidence: 63%

“…It is also possible that ERK phosphorylation acts as a dynamic indicator of recent mGluR activity that may influence the amount of mGluR-LTD. In ΔRG mice (a TSC model), robust enhancement of ERK signaling results in impaired mGluR-LTD (Chevere-Torres et al, 2012), whereas modest activation of ERK and mTORC1 signaling in FXS model mice results in enhanced mGluR-LTD (Hou et al, 2006; Potter et al, 2013; Sharma et al, 2010). …”

Section: Discussionmentioning

confidence: 99%

Necessary, but not sufficient: Insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures

et al. 2014

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Using the rat model of early life seizures (ELS), which has exaggerated mGluR mediated long-term depression of synaptic strength (mGluR-LTD) in adulthood, we probed the signaling cascades underlying mGluR-LTD induction. Several inhibitors completely blocked mGluR-LTD in control but not in ELS rats: the proteasome, the mammalian target of rapamycin (mTOR), S6 kinase (S6K), or L-type voltage-gated calcium channels (L-type VGCC). Inhibition of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) resulted in a near complete block of mGluR-LTD in control rats and a slight reduction of mGluR-LTD in ELS rats. “Autonomous” CaMKII was found to be upregulated in ELS rats, while elevated S6K activity, which is stimulated by mTOR, was described previously. Thus, modulation of each of these factors was necessary for mGluR-LTD induction in control rats, but even their combined, permanent activation in the ELS rats was not sufficient to individually support mGluR-LTD induction following ELS. This implies that while these factors may act sequentially in controls to mediate mGluR-LTD, this is no longer the case after ELS. In contrast, activated ERK was found to be significantly down-regulated in ELS rats. Inhibition of MEK/ERK activation in control rats elevated mGluR-LTD to the exaggerated levels seen in ELS rats. Together, these results elucidate both the mechanisms that persistently enhance mGluR-LTD after ELS and the mechanisms underlying normal mGluR-LTD by providing evidence for multiple, convergent pathways that mediate mGluR-LTD induction. With our prior work, this ties these signaling cascades to the ELS behavioral phenotype that includes abnormal working memory, fear conditioning and socialization.

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“…In mice, loss of Tsc1 or Tsc2 leads to cellular hyperexcitability in vitro and in vivo 44,45 . For example, Tsc1 conditional knockout (cKO) mice show decreased expression of the astrocytic glutamate transporters GLT-1 and GLAST-1, and astrocytic glutamate transport currents are seen in Tsc1 cKO hippocampal slices 45 .…”

Section: Megalencephalymentioning

confidence: 99%

The mTOR signalling cascade: paving new roads to cure neurological disease

2016

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Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR - regulation of cell growth and proliferation, as well as autophagy and cell death - have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic-ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.

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Reduced Juvenile Long-Term Depression in Tuberous Sclerosis Complex Is Mitigated in Adults by Compensatory Recruitment of mGluR5 and Erk Signaling

Abstract: A mouse model of the human genetic disorder tuberous sclerosis complex fails to undergo developmental down-regulation of mGluR5 expression and activation of Erk signaling, probably contributing to the aberrant plasticity and epilepsy in this disease.

Cited by 43 publications

References 50 publications

Tsc1-mTOR signaling controls the structure and function of midbrain dopamine neurons

Tsc1-mTOR signaling controls the structure and function of midbrain dopamine neurons

Necessary, but not sufficient: Insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures

The mTOR signalling cascade: paving new roads to cure neurological disease

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