Activity-Dependent Rapid Local RhoA Synthesis Is Required for Hippocampal Synaptic Plasticity

Briz, Victor; Zhu, Guoqi; Wang, Yubin; Liu, Yan; Avetisyan, Mariam; Bi, Xiaoning; Baudry, Michel

doi:10.1523/jneurosci.2302-14.2015

Cited by 56 publications

(43 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many previous publications showed similar examples in which either loss (Shmerling et al, 1998) or dysfunction (Chen et al, 1999; Hashimoto et al, 1999) of cerebellar granule cells leads to impaired PF-PC transmission and ataxia. In addition, we and another lab previously found that dysregulation of calpain or Akt affects actin polymerization, which is important for synapse formation and function and regulating the shape of the dendritic spines (Briz et al, 2015; Huang et al, 2013). We previously reported that calpain-1 activation was critical for induction of LTP at hippocampal synapses (Wang et al, 2014), and it has been repeatedly proposed that establishment of synaptic contacts during the postnatal period might require a mechanism similar to LTP (Chaudhury et al, 2015).…”

Section: Discussionmentioning

confidence: 83%

Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans

et al. 2016

View full text Add to dashboard Cite

SUMMARY A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous CAPN1 null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knock-out (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1 mediated cleavage of PH domain and Leucine rich repeat Protein Phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis, and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.

show abstract

Section: Discussionmentioning

confidence: 83%

Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Actin polymerization was quantified by measurement of “rhodamine-phalloidin fluorescent enhancement”, as previously described with minor modifications [29]. For details, see Supplementary materials and methods.…”

Section: Methodsmentioning

confidence: 99%

mTORC1–S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice

Sun

Liu

Tran

et al. 2016

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Emerging evidence is implicating abnormal activation of the mechanistic target of rapamycin (mTOR) pathway in several monogenetic neuropsychiatric disorders, including Angelman syndrome (AS), which is caused by deficiency in maternally inherited UBE3A. Using an AS mouse model, we show that semi-chronic rapamycin treatment improves long-term potentiation (LTP) and actin polymerization in hippocampal slices, spine morphology, and fear-conditioning learning. Activity of mTORC1 and of its downstream substrate, S6K1, was increased in hippocampus of AS mice. However, mTORC2 activity, as reflected by PKCα levels, was decreased. Both increased mTORC1 and decreased mTORC2 activity were reversed by semi-chronic rapamycin treatment. Acute treatment of hippocampal slices from AS mice with rapamycin or an S6K1 inhibitor, PF4708671, improved LTP, restored actin polymerization, and normalized mTORC1 and mTORC2 activity. These treatments also reduced Arc levels in AS mice. Treatment with Torin 1, an inhibitor of both mTORC1 and mTORC2, partially rescued LTP and actin polymerization in hippocampal slices from AS mice, while partially impairing them in wild-type (WT) mice. Torin 1 decreased mTORC1 and increased mTORC2 activity in slices from AS mice but inhibited mTORC1 and decreased mTORC2 in WT mice. Finally, an mTORC2 activator, A-443654, increased hippocampal LTP in AS mice and actin polymerization in both WT and AS mice. Collectively, these results indicate that events set in motion by increased mTORC1 and decreased mTORC2 activities, including increased Arc translation and impaired actin remodeling, are crucial in AS pathogenesis. Therefore, selectively targeting these two master kinase complexes may provide new therapeutic approaches for AS treatment.

show abstract

“…Rapamycin treatment results in reduced latephase LTP induced by high-frequency stimulation in the hippocampus; the early phase of LTP is unaffected 5 . Moreover, rapamycin has been shown to block the synaptic potentiation induced by brain-derived neuro trophic factor in hippocampal slices 27 . By contrast, exposure of mouse hippocampal slices to the metabotropic glutamate receptor (mGluR) agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) increased phosphorylation of AKT and mTOR in CA1 and increased mGluR-dependent LTD 28 , and rapamycin prevented DHPG-induced mGluR-mediated LTD 28 .…”

Section: Malformations Of Cortical Development (Mcds)mentioning

confidence: 99%

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

2016

View full text Add to dashboard Cite

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.

show abstract

Activity-Dependent Rapid Local RhoA Synthesis Is Required for Hippocampal Synaptic Plasticity

Cited by 56 publications

References 61 publications

Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans

Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans

mTORC1–S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice

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

Contact Info

Product

Resources

About