Rac-maninoff and Rho-vel: The symphony of Rho-GTPase signaling at excitatory synapses.

Synaptic connections between neurons are essential for every facet of human cognition and are thus regulated with extreme precision. Rho-family GTPases, molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state, comprise a critical feature of synaptic regulation. Rho-GTPases are exquisitely controlled by an extensive suite of activators (GEFs) and inhibitors (GAPs and GDIs) and interact with many different signalling pathways to fulfill their roles in orchestrating the development, maintenance, and plasticity of excitatory synapses of the central nervous system.

The Rac-GEF Tiam1 Promotes Dendrite and Synapse Stabilization of Dentate Granule Cells and Restricts Hippocampal-Dependent Memory Functions.

The dentate gyrus (DG) controls information flow into the hippocampus and is critical for learning, memory, pattern separation, and spatial coding, while DG dysfunction is associated with neuropsychiatric disorders. Despite its importance, the molecular mechanisms regulating DG neural circuit assembly and function remain unclear. Here, we identify the Rac-GEF Tiam1 as an important regulator of DG development and associated memory processes.

Cranial irradiation induces axon initial segment dysfunction and neuronal injury in the prefrontal cortex and impairs hippocampal coupling.

Background: Radiation therapy for brain tumors commonly induces cognitive dysfunction. The prefrontal cortex (PFC) is crucial for a diverse array of cognitive processes, however, its role in radiation-induced cognitive dysfunction is unknown. We previously found that cranial irradiation impairs neuroplasticity along the hippocampal-PFC pathway.

The adhesion-GPCR BAI1 shapes dendritic arbors via Bcr-mediated RhoA activation causing late growth arrest.

Dendritic arbor architecture profoundly impacts neuronal connectivity and function, and aberrant dendritic morphology characterizes neuropsychiatric disorders. Here, we identify the adhesion-GPCR BAI1 as an important regulator of dendritic arborization. BAI1 loss from mouse or rat hippocampal neurons causes dendritic hypertrophy, whereas BAI1 overexpression precipitates dendrite retraction.

An autism-linked missense mutation in SHANK3 reveals the modularity of Shank3 function.

Genome sequencing has revealed an increasing number of genetic variations that are associated with neuropsychiatric disorders. Frequently, studies limit their focus to likely gene-disrupting mutations because they are relatively easy to interpret. Missense variants, instead, have often been undervalued.

Beetle, Dendroides canadensis, antifreeze proteins increased high temperature survivorship in transgenic fruit flies, Drosophila melanogaster.

Paradoxically, some insects have an increased capacity to survive higher temperatures in winter than summer. Possible contributors to this increased heat tolerance in winter could be their sub-zero adaptations (high polyol concentrations, antifreeze proteins, antifreeze glycolipids, etc.).

The Adhesion-GPCR BAI1 Promotes Excitatory Synaptogenesis by Coordinating Bidirectional Trans-synaptic Signaling.

Excitatory synapses are specialized cell-cell contacts located on actin-rich dendritic spines that mediate information flow and storage in the brain. The postsynaptic adhesion-G protein-coupled receptor (A-GPCR) BAI1 is a critical regulator of excitatory synaptogenesis, which functions in part by recruiting the Par3-Tiam1 polarity complex to spines, inducing local Rac1 GTPase activation and actin cytoskeletal remodeling. However, a detailed mechanistic understanding of how BAI1 controls synapse and spine development remains elusive.

Particle Radiation Induced Neurotoxicity in the Central Nervous System.

For patients with primary or metastatic brain tumors, radiation therapy plays a central role in treatment. However, despite its efficacy, cranial radiation is associated with a range of side effects ranging from mild cognitive impairment to overt brain necrosis. Given the negative effects on patient quality of life, radiation-induced neurotoxicities have been the subject of intense study for decades.

Radiation induces age-dependent deficits in cortical synaptic plasticity.

Background: Radiation-induced cognitive dysfunction is a significant side effect of cranial irradiation for brain tumors. Clinically, pediatric patients are more vulnerable than adults. However, the underlying mechanisms of dysfunction, including reasons for age dependence, are still largely unknown.

Memantine prevents acute radiation-induced toxicities at hippocampal excitatory synapses.

Background: Memantine has shown clinical utility in preventing radiation-induced cognitive impairment, but the mechanisms underlying its protective effects remain unknown. We hypothesized that abnormal glutamate signaling causes radiation-induced abnormalities in neuronal structure and that memantine prevents synaptic toxicity.

Methods: Hippocampal cultures expressing enhanced green fluorescent protein were irradiated or sham-treated and their dendritic spine morphology assessed at acute (minutes) and later (days) times using high-resolution confocal microscopy.

Upper lethal temperatures in three cold-tolerant insects are higher in winter than in summer.

Upper lethal temperatures (ULTs) of cold-adapted insect species in winter have not been previously examined. We anticipated that as the lower lethal temperatures (LLTs) decreased (by 20-30°C) with the onset of winter, the ULTs would also decrease accordingly. Consequently, given the recent increases in winter freeze-thaw cycles and warmer winters due to climate change, it became of interest to determine whether ambient temperatures during thaws were approaching ULTs during the cold seasons.

RhoGTPases Spread the Word for Synaptic Crosstalk.

Excitatory synaptic strengthening and the corresponding enlargement of dendritic spines are thought to be essential for learning and memory. In two recent Nature papers, Harward et al. (2016) and Hedrick et al.

Ice nucleation of an insect lipoprotein ice nucleator (LPIN) correlates with retardation of the hydrogen bond dynamics at the myo-inositol ring.

Remarkably little is known about the mechanism of action of ice nucleation proteins (INPs), although their ability to trigger ice nucleation could be used in a broad variety of applications. We present CD measurements of an insect lipoprotein ice nucleator (LPIN) which show that the lipoproteins consist of a high amount of β-structures (35%). Terahertz absorption spectroscopy is used to probe the influence of the LPIN on the H-bond network dynamics.

Efficiency of beetle (Dendroides canadensis) recombinant antifreeze protein for buffalo semen freezability and fertility.

Overwintering larvae of the beetle Dendroides canadensis produce potent antifreeze proteins to inhibit inoculative freezing and promote supercooling. We hypothesized that addition of Dendroides canadensis recombinant antifreeze proteins (DAFPs) in the extender will improve the quality and fertility of cryopreserved Nili-Ravi buffalo (Bubalus bubalis) sperm. The study was divided into two parts: (1) Evaluation of the effect of DAFPs on the quality of frozen-thawed buffalo bull sperm and (2) Examination of the fertilizing ability of frozen-thawed buffalo bull sperm.

Antifreeze proteins govern the precipitation of trehalose in a freezing-avoiding insect at low temperature.

The remarkable adaptive strategies of insects to extreme environments are linked to the biochemical compounds in their body fluids. Trehalose, a versatile sugar molecule, can accumulate to high levels in freeze-tolerant and freeze-avoiding insects, functioning as a cryoprotectant and a supercooling agent. Antifreeze proteins (AFPs), known to protect organisms from freezing by lowering the freezing temperature and deferring the growth of ice, are present at high levels in some freeze-avoiding insects in winter, and yet, paradoxically are found in some freeze-tolerant insects.

Blocking rapid ice crystal growth through nonbasal plane adsorption of antifreeze proteins.

Antifreeze proteins (AFPs) are a unique class of proteins that bind to growing ice crystal surfaces and arrest further ice growth. AFPs have gained a large interest for their use in antifreeze formulations for water-based materials, such as foods, waterborne paints, and organ transplants. Instead of commonly used colligative antifreezes such as salts and alcohols, the advantage of using AFPs as an additive is that they do not alter the physicochemical properties of the water-based material.

Emerging Roles of BAI Adhesion-GPCRs in Synapse Development and Plasticity.

Synapses mediate communication between neurons and enable the brain to change in response to experience, which is essential for learning and memory. The sites of most excitatory synapses in the brain, dendritic spines, undergo rapid remodeling that is important for neural circuit formation and synaptic plasticity. Abnormalities in synapse and spine formation and plasticity are associated with a broad range of brain disorders, including intellectual disabilities, autism spectrum disorders (ASD), and schizophrenia.

Investigation of the Ice-Binding Site of an Insect Antifreeze Protein Using Sum-Frequency Generation Spectroscopy.

We study the ice-binding site (IBS) of a hyperactive antifreeze protein from the beetle Dendroides canadensis (DAFP-1) using vibrational sum-frequency generation spectroscopy. We find that DAFP-1 accumulates at the air-water interface due to the hydrophobic character of its threonine-rich IBS while retaining its highly regular β-helical fold. We observe a narrow band at 3485 cm(-1) that we assign to the O-H stretch vibration of threonine hydroxyl groups of the IBS.

Animal ice-binding (antifreeze) proteins and glycolipids: an overview with emphasis on physiological function.

Ice-binding proteins (IBPs) assist in subzero tolerance of multiple cold-tolerant organisms: animals, plants, fungi, bacteria etc. IBPs include: (1) antifreeze proteins (AFPs) with high thermal hysteresis antifreeze activity; (2) low thermal hysteresis IBPs; and (3) ice-nucleating proteins (INPs). Several structurally different IBPs have evolved, even within related taxa.

Mechanisms for spatiotemporal regulation of Rho-GTPase signaling at synapses.

Synapses mediate information flow between neurons and undergo plastic changes in response to experience, which is critical for learning and memory. Conversely, synaptic defects impair information processing and underlie many brain pathologies. Rho-family GTPases control synaptogenesis by transducing signals from extracellular stimuli to the cytoskeleton and nucleus.

New functions and signaling mechanisms for the class of adhesion G protein-coupled receptors.

The class of adhesion G protein-coupled receptors (aGPCRs), with 33 human homologs, is the second largest family of GPCRs. In addition to a seven-transmembrane α-helix-a structural feature of all GPCRs-the class of aGPCRs is characterized by the presence of a large N-terminal extracellular region. In addition, all aGPCRs but one (GPR123) contain a GPCR autoproteolysis-inducing (GAIN) domain that mediates autoproteolytic cleavage at the GPCR autoproteolysis site motif to generate N- and a C-terminal fragments (NTF and CTF, respectively) during protein maturation.

Dynamic control of excitatory synapse development by a Rac1 GEF/GAP regulatory complex.

The small GTPase Rac1 orchestrates actin-dependent remodeling essential for numerous cellular processes including synapse development. While precise spatiotemporal regulation of Rac1 is necessary for its function, little is known about the mechanisms that enable Rac1 activators (GEFs) and inhibitors (GAPs) to act in concert to regulate Rac1 signaling. Here, we identify a regulatory complex composed of a Rac-GEF (Tiam1) and a Rac-GAP (Bcr) that cooperate to control excitatory synapse development.

Molecular recognition of methyl α-D-mannopyranoside by antifreeze (glyco)proteins.

Antifreeze proteins and glycoproteins [AF(G)Ps] have been well-known for more than three decades for their ability to inhibit the growth and recrystallization of ice through binding to specific ice crystal faces, and they show remarkable structural compatibility with specific ice crystal faces. Here, we show that the crystal growth faces of methyl α-D-mannopyranoside (MDM), a representative pyranose sugar, also show noteworthy structural compatibility with the known periodicities of AF(G)Ps. We selected fish AFGPs (AFGP8, AFGP1-5), and a beetle AFP (DAFP1) with increasing antifreeze activity as potential additives for controlling MDM crystal growth.

The role of sulfates on antifreeze protein activity.

In the present study, we have investigated the effect of sodium sulfate (Na2SO4) buffer on the antifreeze activity of DAFP-1, the primary AFP in the hemolymph of the beetle Dendroides canadensis. In contrast to previous studies, we found evidence that sodium sulfate does not suppress antifreeze activity of DAFP-1. Terahertz absorption spectroscopy (THz) studies were combined with molecular dynamics (MD) simulations to investigate the change in collective hydrogen bond dynamics in the vicinity of the AFP upon addition of sodium sulfate.

Recombinant Dendroides canadensis antifreeze proteins as potential ingredients in cryopreservation solutions.

Expanding cryopreservation methods to include a wider range of cell types, such as those sensitive to freezing, is needed for maintaining the viability of cell-based regenerative medicine products. Conventional cryopreservation protocols, which include use of cryoprotectants such as dimethylsulfoxide (Me2SO), have not prevented ice-induced damage to cell and tissue matrices during freezing. A family of antifreeze proteins (AFPs) produced in the larvae of the beetle, Dendroides canadensis allow this insect to survive subzero temperatures as low as -26°C.