Caspases in synaptic plasticity

Caspases are a family of cysteine proteases that play key roles in programmed cell death (apoptosis). Mounting evidence in recent years shows that caspases also have important non-apoptotic functions in multiple cellular processes, such as synaptic plasticity, dendritic development, learning and memory. In this article, we review the studies on the non-apoptotic functions of caspases in neurons, with a focus on their roles in synaptic plasticity, learning and memory and neurodegeneration

Direct interaction of Frizzled-1, -2, -4, and -7 with PDZ domains of PSD-95

AbstractIn Drosophila, the frizzled gene plays a critical role in the establishment of tissue polarity, but the function of the Frizzled family of proteins in mammals is largely unknown. Recent evidence suggested that Frizzleds are receptors for the Wnt family of secreted glycoproteins which are involved in cell fate determination. However, it is unclear how Frizzled receptors transduce Wnt signals to intracellular signaling components. Here we show that the mouse Frizzled-1, -2, -4 and -7 can bind to proteins of the PSD-95 family, which are implicated in the assembly and localization of multiprotein signaling complexes in the brain. Moreover, PSD-95 can form a ternary complex with Frizzled-2 and the adenomatous polyposis coli protein, a negative regulator of Wnt signaling, suggesting that members of the PSD-95 family may serve to recruit intracellular signaling molecules of the Wnt/Frizzled pathway into the vicinity of the receptor

Challenges to the DGP Model from Horizon-Scale Growth and Geometry

We conduct a Markov Chain Monte Carlo study of the Dvali-Gabadadze-Porrati (DGP) self-accelerating braneworld scenario given the cosmic microwave background (CMB) anisotropy, supernovae and Hubble constant data by implementing an effective dark energy prescription for modified gravity into a standard Einstein-Boltzmann code. We find no way to alleviate the tension between distance measures and horizon scale growth in this model. Growth alterations due to perturbations propagating into the bulk appear as excess CMB anisotropy at the lowest multipoles. In a flat cosmology, the maximum likelihood DGP model is nominally a 5.3 sigma poorer fit than Lambda CDM. Curvature can reduce the tension between distance measures but only at the expense of exacerbating the problem with growth leading to a 4.8 sigma result that is dominated by the low multipole CMB temperature spectrum. While changing the initial conditions to reduce large scale power can flatten the temperature spectrum, this also suppresses the large angle polarization spectrum in violation of recent results from WMAP5. The failure of this model highlights the power of combining growth and distance measures in cosmology as a test of gravity on the largest scales.Comment: 12 pages, 7 figures, 4 tables, minor revisions reflect PRD published versio

Lexical-Semantic Organization in Bilingually Developing Deaf Children With ASL-Dominant Language Exposure: Evidence From a Repeated Meaning Association Task

This study compared the lexical-semantic organization skills of bilingually developing deaf children in American Sign Language (ASL) and English with those of a monolingual hearing group. A repeated meaning-association paradigm was used to assess retrieval of semantic relations in deaf 6–10-year-olds exposed to ASL from birth by their deaf parents, with responses coded as syntagmatic or paradigmatic. Deaf children's responses in ASL and English were compared at the within-group level, and their ASL was compared to the English responses of age-matched monolingual hearing children. Finally, the two groups were compared on their semantic performance in English. Results showed similar patterns for deaf children's responses in ASL and English to those of hearing monolinguals, but subtle language differences were also revealed. These findings suggest that sign bilinguals’ language development in ASL and English is driven by similar underlying learning mechanisms rooted in the development of semantic frameworks

Weighing Neutrinos with Galaxy Cluster Surveys

Large future galaxy cluster surveys, combined with cosmic microwave background observations, can achieve a high sensitivity to the masses of cosmologically important neutrinos. We show that a weak lensing selected sample of ~100,000 clusters could tighten the current upper bound on the sum of masses of neutrino species by an order of magnitude, to a level of 0.03 eV. Since this statistical sensitivity is below the best existing lower limit on the mass of at least one neutrino species, a future detection is likely, provided that systematic errors can be controlled to a similar level.Comment: 4 pages, 1 figure, version accepted for publication in PR

Cosmological Information in Weak Lensing Peaks

Recent studies have shown that the number counts of convergence peaks N(kappa) in weak lensing (WL) maps, expected from large forthcoming surveys, can be a useful probe of cosmology. We follow up on this finding, and use a suite of WL convergence maps, obtained from ray-tracing N-body simulations, to study (i) the physical origin of WL peaks with different heights, and (ii) whether the peaks contain information beyond the convergence power spectrum P_ell. In agreement with earlier work, we find that high peaks (with amplitudes >~ 3.5 sigma, where sigma is the r.m.s. of the convergence kappa) are typically dominated by a single massive halo. In contrast, medium-height peaks (~0.5-1.5 sigma) cannot be attributed to a single collapsed dark matter halo, and are instead created by the projection of multiple (typically, 4-8) halos along the line of sight, and by random galaxy shape noise. Nevertheless, these peaks dominate the sensitivity to the cosmological parameters w, sigma_8, and Omega_m. We find that the peak height distribution and its dependence on cosmology differ significantly from predictions in a Gaussian random field. We directly compute the marginalized errors on w, sigma_8, and Omega_m from the N(kappa) + P_ell combination, including redshift tomography with source galaxies at z_s=1 and z_s=2. We find that the N(kappa) + P_ell combination has approximately twice the cosmological sensitivity compared to P_ell alone. These results demonstrate that N(kappa) contains non-Gaussian information complementary to the power spectrum.Comment: 24 pages, 12 figures, 14 tables. Accepted for publication in PRD (version before proofs

Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons

PSD-95 (postsynaptic density 95) is a postsynaptic scaffolding protein that links NMDA receptors to the cytoskeleton and signaling molecules. The N-terminal domain of PSD-95 is involved in the synaptic targeting and clustering of PSD-95 and in the clustering of NMDA receptors at synapses. The N-terminal domain of PSD-95 contains three consensus phosphorylation sites for cyclin-dependent kinase 5 (cdk5), a proline-directed serine-threonine kinase essential for brain development and implicated in synaptic plasticity, dopamine signaling, cocaine addiction, and neurodegenerative disorders. We report that PSD-95 is phosphorylated in the N-terminal domain by cdk5 in vitro and in vivo, and that this phosphorylation is not detectable in brain lysates of cdk5-/- mice. N-terminal phosphorylated PSD-95 is found in PSD fractions together with cdk5 and its activator, p35, suggesting a role for phosphorylated PSD-95 at synapses. In heterologous cells, coexpression of active cdk5 reduces the ability of PSD-95 to multimerize and to cluster neuronal ion channels, two functions attributed to the N-terminal domain of PSD-95. Consistent with these observations, the lack of cdk5 activity in cultured neurons results in larger clusters of PSD-95. In cdk5-/- cortical neurons, more prominent PSD-95 immunostained clusters are observed than in wild-type neurons. In hippocampal neurons, the expression of DNcdk5 (inactive form of cdk5) or of the triple alanine mutant (T19A, S25A, S35A) full-length PSD-95 results in increased PSD-95 cluster size. These results identify cdk5-dependent phosphorylation of the N-terminal domain of PSD-95 as a novel mechanism for regulating the clustering of PSD-95. Moreover, these observations support the possibility that cdk5-dependent phosphorylation of PSD-95 dynamically regulates the clustering of PSD-95/NMDA receptors at synapses, thus providing a possible mechanism for rapid changes in density and/or number of receptor at synapses

The Effects of Moral Obligations to Others and Others\u27 Influence on Veterinarians\u27 Attitudes toward and Recommendations to Utilize Antibiotics in Feedlot Cattle

Decisions to behave in particular ways depend on beliefs, social norms, perceived constraints, and attitudes. Recently, this perspective has been expanded to consider the role of moral obligations in such decisions. Largely ignored are the possible interrelations among moral obligations to significant others and significant others’ influences as they interact to affect decisions. This is of particular interest when a strong moral obligation toward a significant other is associated with strong behavioral expectations by that same significant other. We investigated the interrelations among moral obligations to, and behavioral expectations from, 11 types of significant others in the cattle feeding industry to determine their joint influences on attitudes toward antibiotic use and recommendations for antibiotics in feedlot cattle, drawing data from a random sample of feedlot veterinarians (n=103). Results show that subjective norms and a sense of moral obligation affect both the attitudes toward, and the recommendations for, the use of antibiotics in feedlot cattle. We found several significant interactions among subjective norms and moral obligations, which suggests that perceived moral obligations to peers, clients, and the regulatory norm-setting sector associated with the feedlot industry increase the impact of social pressures from those sectors on the recommendation to use antibiotics in acutely sick, chronically sick, and high-risk feedlot cattle

A Septin-Dependent Diffusion Barrier at Dendritic Spine Necks

Excitatory glutamatergic synapses at dendritic spines exchange and modulate their receptor content via lateral membrane diffusion. Several studies have shown that the thin spine neck impedes the access of membrane and solute molecules to the spine head. However, it is unclear whether the spine neck geometry alone restricts access to dendritic spines or if a physical barrier to the diffusion of molecules exists. Here, we investigated whether a complex of septin cytoskeletal GTPases localized at the base of the spine neck regulates diffusion across the spine neck. We found that, during development, a marker of the septin complex, Septin7 (Sept7), becomes localized to the spine neck where it forms a stable structure underneath the plasma membrane. We show that diffusion of receptors and bulk membrane, but not cytoplasmic proteins, is slower in spines bearing Sept7 at their neck. Finally, when Sept7 expression was suppressed by RNA interference, membrane molecules explored larger membrane areas. Our findings indicate that Sept7 regulates membrane protein access to spines

Autophosphorylated CaMKIIα Acts as a Scaffold to Recruit Proteasomes to Dendritic Spines

The molecular mechanisms regulating the ubiquitin proteasome system (UPS) at synapses are poorly understood. We report that CaMKIIα—an abundant postsynaptic protein kinase—mediates the activity-dependent recruitment of proteasomes to dendritic spines in hippocampal neurons. CaMKIIα is biochemically associated with proteasomes in the brain. CaMKIIα translocation to synapses is required for activity-induced proteasome accumulation in spines, and is sufficient to redistribute proteasomes to postsynaptic sites. CaMKIIα autophosphorylation enhances its binding to proteasomes and promotes proteasome recruitment to spines. In addition to this structural role, CaMKIIα stimulates proteasome activity by phosphorylating proteasome subunit Rpt6 on Serine 120. However, CaMKIIα translocation, but not its kinase activity, is required for activity-dependent degradation of polyubiquitinated proteins in spines. Our findings reveal a scaffolding role of postsynaptic CaMKIIα in activity-dependent proteasome redistribution, which is commensurate with the great abundance of CaMKIIα in synapses.Howard Hughes Medical Institute (Investigator