p140Cap Regulates Memory and Synaptic Plasticity through Src-Mediated and Citron-N-Mediated Actin Reorganization

Repetto, Daniele; Camera, Paola; Melani, Riccardo; Morello, Noemi; Russo, Isabella; Calcagno, Eleonora; Tomasoni, Romana; Bianchi, F.; Berto, Gaia; Giustetto, Maurizio; Berardi, Nicoletta; Pizzorusso, Tommaso; Matteoli, Michela; Stefano, Paola Di; Missler, Markus; Turco, Emilia; Cunto, Ferdinando Di; Defilippi, Paola

doi:10.1523/jneurosci.2341-13.2014

Cited by 48 publications

(84 citation statements)

References 49 publications

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“…Given the crucial role of actin dynamics in neuronal morphology not only during spine morphogenesis but also in activity-dependent structural plasticity, and a recently identified function of p140Cap in learning and long-term potentiation/long-term depression using p140Cap-knockout mice [37], our results raise the possibility that endophilin A1 is also involved in regulation of synaptic plasticity and memory.…”

Section: Discussionmentioning

confidence: 66%

“…It is also reported that overstimulation of NMDA receptors removes cortactin and thereby collapses dendritic spines, whereas stimulation with neurotrophic factors redistributes cortactin from dendritic shafts to spines to solidify synaptic transmission [35]. As p140Cap is able to regulate cortactin phosphorylation by Src and associate with cortactin in neurons [26,36,37], next we investigated whether endophilin A1 regulates reorganization of the actin cytoskeleton to drive spine morphogenesis and whether cortactin acts downstream of the endophilin A1-p140Cap pathway.…”

Section: Endophilin A1 Regulates Actin Cytoskeleton Reorganization Inmentioning

confidence: 99%

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Endophilin A1 regulates dendritic spine morphogenesis and stability through interaction with p140Cap

et al. 2015

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Dendritic spines are actin-rich membrane protrusions that are the major sites of excitatory synaptic input in the mammalian brain, and their morphological plasticity provides structural basis for learning and memory. Here we report that endophilin A1, with a well-established role in clathrin-mediated synaptic vesicle endocytosis at the presynaptic terminal, also localizes to dendritic spines and is required for spine morphogenesis, synapse formation and synaptic function. We identify p140Cap, a regulator of cytoskeleton reorganization, as a downstream effector of endophilin A1 and demonstrate that disruption of their interaction impairs spine formation and maturation. Moreover, we demonstrate that knockdown of endophilin A1 or p140Cap impairs spine stabilization and synaptic function. We further show that endophilin A1 regulates the distribution of p140Cap and its downstream effector, the F-actin-binding protein cortactin as well as F-actin enrichment in dendritic spines. Together, these results reveal a novel function of postsynaptic endophilin A1 in spine morphogenesis, stabilization and synaptic function through the regulation of p140Cap.

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Section: Discussionmentioning

confidence: 66%

Section: Endophilin A1 Regulates Actin Cytoskeleton Reorganization Inmentioning

confidence: 99%

Endophilin A1 regulates dendritic spine morphogenesis and stability through interaction with p140Cap

et al. 2015

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“…The integrity of this macromolecular complex appears to be fundamental for both structural and functional synaptic plasticity. Indeed, p140Cap − / − mice display similar defects in episodic memory and are impaired in LTP and in LTD. 59 These data provide new mechanistic insights as to SNAP-25 involvement in synaptopathies that go beyond the protein's known roles in presynaptic function, indicating a protein role as a postsynaptic structural hub. Indeed, the activity-driven spine remodeling is defective in neuronal networks constitutively developing in the presence of reduced levels of SNAP-25, as it might presumably occur in human pathologies, such as schizophrenia, where both a reduction of SNAP-25 expression 15 and a reduction in dendritic spine density 60 have been described.…”

Section: Discussionmentioning

confidence: 84%

“…SNAP-25 wild-type and SNAP-25 heterozygous male mice 61 were housed in cages with free access to food and water at 22°C and with a 12-h alternating light/dark cycle. Genotyping was performed by PCR as described in Washbourne et al 61 p140Cap wild-type and knockout mice strain is described in Repetto et al 59 Cell cultures. Mouse hippocampal or rat hippocampal and cortical neurons were prepared from E18 fetal SNAP-25 heterozygous (Het) or wild-type (wt) littermates C57BL/6 mice as described in Bartlett and Banker 62 with slight modifications.…”

Section: Methodsmentioning

confidence: 99%

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

et al. 2015

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Impairment of synaptic function can lead to neuropsychiatric disorders collectively referred to as synaptopathies. The SNARE protein SNAP-25 is implicated in several brain pathologies and, indeed, brain areas of psychiatric patients often display reduced SNAP-25 expression. It has been recently found that acute downregulation of SNAP-25 in brain slices impairs long-term potentiation; however, the processes through which this occurs are still poorly defined. We show that in vivo acute downregulation of SNAP-25 in CA1 hippocampal region affects spine number. Consistently, hippocampal neurons from SNAP-25 heterozygous mice show reduced densities of dendritic spines and defective PSD-95 dynamics. Finally, we show that, in brain, SNAP-25 is part of a molecular complex including PSD-95 and p140Cap, with p140Cap being capable to bind to both SNAP-25 and PSD-95. These data demonstrate an unexpected role of SNAP-25 in controlling PSD-95 clustering and open the possibility that genetic reductions of the protein levels -as occurring in schizophrenia -may contribute to the pathology through an effect on postsynaptic function and plasticity. Cell Death and Differentiation (2015) 22, 1425-1436 doi:10.1038/cdd.2014 published online 13 February 2015 Synapses are complex cellular junctions specialized for communication between neurons. Epidemiological and genetic studies demonstrated that deficiencies in synapse function 1 are implicated in a wide range of brain disorders, including neurodegenerative 2 and psychiatric diseases such as schizophrenia 3,4 and autism. 5,6 A hallmark of synaptic specializations is their dependence on highly organized complexes of proteins that interact with each other. Therefore, the loss or modification of key synaptic proteins might directly affect the properties of such networks and, ultimately, synaptic function.SNAP-25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis 7,8 and which has a role in the regulation of voltage-gated calcium channels. 9,10 The SNAP25 gene has been associated with attention deficit hyperactivity disorder (ADHD) 11,12 and with schizophrenia. 13,14 Consistently, SNAP-25 levels are lower in the hippocampus 15 and in the frontal lobe 16 of patients with schizophrenia. DNA variants of the SNAP25 gene that associate with ADHD are also associated with reduced expression level of the transcript in prefrontal cortex. 17 Finally, reduction of SNAP-25 levels has been found to cause neurodegeneration in mice lacking the synaptic vesicle protein Cysteine-string protein-α, possibly due to the impaired SNARE-complex assembly produced by the decreased SNAP-25. 18 The mechanisms by which reduced SNAP-25 expression may result in a psychiatric disease are still undefined, although alterations in neurotransmitter release have been indicated as potential causative processes. 19,20 Recently an unexpected postsynaptic role of SNAP-25 has been described, with the protein controlling NMDA and kainate receptor trafficking. 21 Furthermore, it has been lately ...

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“…3E). Based on recent studies indicating that Srcin1 plays a critical role in regulating synaptic plasticity in the hippocampus and spatial memory (28,29), and on the fact that Srcin1 is the most highly regulated among the genes that show reciprocal changes in H3R2me2a and H3K4me3, we focused subsequent attention on cocaine regulation of Srcin1.…”

Section: Significancementioning

confidence: 99%

Histone arginine methylation in cocaine action in the nucleus accumbens

Damez-Werno

Sun

Scobie

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanismssuch as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.histone arginine (R) methylation | drug addiction | medium spiny neurons | ChIP-seq | Src R epeated cocaine exposure is marked by persistent changes in gene expression within the nucleus accumbens (NAc), a central component of the brain's reward circuitry (1, 2). Important aspects of cocaine action appear to be mediated by changes in gene transcription via chromatin regulatory mechanisms such as histone acetylation or methylation on Lys (K) residues (3-11). However, in contrast to K methylation, the functional role of histone Arg (R) methylation remains underexplored in addiction models and poorly understood in the brain in general.The methylation of R residues is catalyzed by the protein R methyltransferase (PRMT) family of enzymes, which can generate different methylated R states with diverse functional consequences, including monomethylarginine (MMA) and dimethylarginine (DMA) residues, the latter of which can be either asymmetric (aDMA) or symmetric (sDMA). PRMTs that catalyze aDMA are designated type I, and those that generate sDMA are designated type II (12, 13). Histone tails are prime targets for these PRMTs, and R methylation induces alterations in chromatin architecture, either condensing or relaxing its structure, thereby creating binding sites for regulatory proteins that contain specialized binding domains (14, 15).PRMT6, a nuclear enzyme that modifies histone tails, is the primary enzyme responsible for asymmetric dimethylation of R2 on histone H3 (H3R2me2a) in mammalian cells (14,16). The H3R2me2a mark is thought to be repressive in nature because of...

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p140Cap Regulates Memory and Synaptic Plasticity through Src-Mediated and Citron-N-Mediated Actin Reorganization

Cited by 48 publications

References 49 publications

Endophilin A1 regulates dendritic spine morphogenesis and stability through interaction with p140Cap

Endophilin A1 regulates dendritic spine morphogenesis and stability through interaction with p140Cap

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

Histone arginine methylation in cocaine action in the nucleus accumbens

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