Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies

Papale, Alessandro; d’Isa, Raffaele; Menna, Elisabetta; Cerovic, Milica; Solari, Nicoletta; Hardingham, Neil Robert; Cambiaghi, Marco; Cursi, Marco; Barbacid, Mariano; Leocani, Letizia; Fasano, Stefania; Matteoli, Michela; Brambilla, Riccardo

doi:10.1016/j.biopsych.2016.06.016

Cited by 32 publications

(58 citation statements)

References 59 publications

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“…5B). Since long-term plasticity (LTP) induced by theta-burst stimulation (TBS) is impaired in Nf1 8, 25 , Ptpn11 10 , Spred1 mice 11 and conditional Kras G12V mice 26 (see Table 1), we tested LTP induced by a theta-burst stimulation protocol and a high frequency (100 Hz) stimulation protocol. Notably, both TBS-induced LTP and 100Hz-induced was similar between genotypes (TBS: F 1,20 = 0.92, P = 0.51; 100 Hz: F 1,14 = 0.80, P = 0.61; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, a closer look at the specific cellular mechanisms reveals substantial differences between the RASopathy mouse models. For instance, neither the cell-type specific increase of inhibition found in Nf1 mutants 24 and a conditional Kras G12V mutant 26 , nor the increase of glutamatergic synaptic transmission observed in the NS model 10 were observed in HRas G12V/G12V mice. In addition, we and others showed that LTP induced by theta-burst stimulation is impaired in all RASopathy mouse models published so far: Nf1 8, 25 , Ptpn11 10 , Spred1 mice 11 and conditional Kras G12V mice 26 .…”

Section: Discussionmentioning

confidence: 96%

“…Surprisingly, even though we observed that the mGluR-LTD deficit in HRas G12V/G12V mice can be rescued by a lower concentration of MEK inhibitor, treatment of HRas G12V/G12V mice with 2 mg/kg of PD0325901 (a MEK-inhibitor which has good bioavailability and is currently in clinical trials) 9, 33–35 successfully restored pERK levels but was insufficient to rescue the spatial learning impairment. Recently, it was also shown that treating adult conditional KRas G12V mice with PD0325901 failed to rescue the behavioural phenotype 26 . There are several possible explanations for our failure to rescue the behavioural phenotype of HRas G12V/G12V mice.…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models

Schreiber

Grimbergen

Overwater

et al. 2017

Sci Rep

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RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRas G12V/G12V mice. HRas G12V/G12V mice showed robust upregulation of ERK signaling, neuronal hypertrophy, increased brain volume, spatial learning deficits, and impaired mGluR-dependent long-term depression (LTD). In contrast, long-term potentiation (LTP), which is affected in other RASopathy mouse models was unaffected. Treatment with lovastatin, a HMG-CoA-Reductase inhibitor which has been shown to rescue the behavioral phenotypes of mouse models of NF1 and Noonan syndrome, was unable to restore ERK signaling and the cognitive deficits of HRas G12V/G12V mice. Administration of a potent mitogen-activated protein kinase (MEK) inhibitor rescued the ERK upregulation and the mGluR-LTD deficit of HRas G12V/G12V mice, but failed to rescue the cognitive deficits. Taken together, this study indicates that the fundamental molecular and cellular mechanisms underlying the cognitive aspects of different RASopathies are remarkably distinct, and may require disease specific treatments.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models

Schreiber

Grimbergen

Overwater

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Indeed, it has been shown that the use of Ras-ERK inhibitors can reverse some of the associated symptoms in animal models (Lee et al, 2014; Papale et al., 2016). Thus, further development of the tools outlined here may not only facilitate the investigation of the neurobiological bases of drug addiction, but may possibly lead to the development of pharmacotherapies for the treatment of other neuropsychiatric conditions.…”

Section: Discussionmentioning

confidence: 99%

Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

Papale

Morella

Indrigo

et al. 2016

eLife

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Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction.DOI: http://dx.doi.org/10.7554/eLife.17111.001

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“…The clear effect on synaptic plasticity mediated by RB5 in brain slices prompted us to investigate whether a single administration of this ERK enhancing peptide could improve cognition in normal mice. In the widely used novel object recognition (NOR) test 22,23 , a single systemic RB5 administration resulted in a sustained memory consolidation (Fig. 4c).…”

Section: Resultsmentioning

confidence: 99%

Modulation of ERK1/MAPK3 potentiates ERK nuclear signalling, facilitates neuronal cell survival and improves memory in mouse models of neurodegenerative disorders

Indrigo

Morella

Orellana

et al. 2018

Preprint

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Cell signalling mechanisms are central to neuronal activity and their dysregulation may lead to neurodegenerative processes and associated cognitive decline. So far, a major effort has been directed toward the dissection of disease specific pathways with the still unmet promise to develop precision medicine strategies. With a different approach, here we show that a selective genetic potentiation of neuronal ERK signalling prevents cell death in vitro and in vivo in the mouse brain while ERK attenuation does the opposite. This neuroprotective effect can also be induced pharmacologically by a cell permeable peptide mimicking the loss of ERK1 MAP kinase, leading to a selective enhancement of ERK2 mediated nuclear cell signalling. The drug treatment prevents neurodegeneration in mouse models of Huntington’s (HD), Alzheimer’s (AD), and Parkinson’s disease (PD). Importantly, the selective potentiation of ERK2 signalling facilitates both structural and synaptic plasticity, enhances cognition in healthy mice and rescues mild cognitive impairments in both models of AD and HD. Altogether, our observation truly represents a remarkable example of a shared molecular mechanism across multiple neurodegenerative disorders and a potentially valuable therapeutic target for neuro-enhancement.

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Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies

Cited by 32 publications

References 59 publications

Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models

Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models

Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

Modulation of ERK1/MAPK3 potentiates ERK nuclear signalling, facilitates neuronal cell survival and improves memory in mouse models of neurodegenerative disorders

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