In vivo axonal transport deficits in a mouse model of fronto-temporal dementia.

Background: Axonal transport is vital for neurons and deficits in this process have been previously reported in a few mouse models of Alzheimer's disease prior to the appearance of plaques and tangles. However, it remains to be determined whether axonal transport is defective prior to the onset of neurodegeneration. The rTg4510 mouse, a fronto-temporal dementia and parkinsonism-17 (FTDP-17) tauopathy model, over-express tau-P301L mutation found in familial forms of FTDP-17, in the forebrain driven by the calcium-calmodulin kinase II promoter.

Dampened dopamine-mediated neuromodulation in prefrontal cortex of fragile X mice.

Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive-compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity.

The tyrosine phosphatase STEP constrains amygdala-dependent memory formation and neuroplasticity.

STriatal-Enriched protein tyrosine Phosphatase (STEP; PTPN5) is expressed in brain regions displaying adult neuroplasticity. STEP modulates neurotransmission by dephosphorylating regulatory tyrosine residues on its substrates. In this way, STEP inactivates extracellular-signal-regulated kinase 1/2 (ERK1/2), limiting the duration and spatial distribution of ERK signaling.

Spatially distinct actions of metabotropic glutamate receptor activation in dorsal lateral geniculate nucleus.

Thalamocortical neurons in the dorsal lateral geniculate nucleus (dLGN) dynamically communicate visual information from the retina to the neocortex, and this process can be modulated via activation of metabotropic glutamate receptors (mGluRs). Neurons within dLGN express different mGluR subtypes associated with distinct afferent synaptic pathways; however, the physiological function of this organization is unclear. We report that the activation of mGluR(5), which are located on presynaptic dendrites of local interneurons, increases GABA output that in turn produces an increased inhibitory activity on proximal but not distal dendrites of dLGN thalamocortical neurons.

Transport of animals between rooms: a little-noted aspect of laboratory procedure that may interfere with memory.

This study investigated the effects of transporting animals from the experimental room to the animal facility in between experimental sessions, a procedure routinely employed in experimental research, on long-term social recognition memory. By using the intruder-resident paradigm, independent groups of Wistar rats exposed to a 2-h encounter with an adult intruder were transported from the experimental room to the animal facility either 0.5 or 6h after the encounter.

Striatal-enriched protein tyrosine phosphatase (STEP) knockout mice have enhanced hippocampal memory.

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that opposes synaptic strengthening by the regulation of key synaptic signaling proteins. Previous studies suggest a possible role for STEP in learning and memory. To demonstrate the functional importance of STEP in learning and memory, we generated STEP knockout (KO) mice and examined the effect of deletion of STEP on behavioral performance, as well as the phosphorylation and expression of its substrates.

The role of STEP in Alzheimer's disease.

Amyloid beta (Aβ), the putative causative agent in Alzheimer's disease, is known to affect glutamate receptor trafficking. Previous studies have shown that Aβ downregulates the surface expression of N-methyl D-aspartate type glutamate receptors (NMDARs) by the activation of STriatal-Enriched protein tyrosine Phosphatase 61 (STEP₆₁). More recent findings confirm that STEP₆₁ plays an important role in Aβ-induced NMDAR endocytosis.

Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61.

Amyloid beta (Abeta) is involved in the etiology of Alzheimer's disease (AD) and may contribute to cognitive deficits by increasing internalization of ionotropic glutamate receptors. Striatal-enriched protein tyrosine phosphatase 61 (STEP(61)), which is targeted in part to the postsynaptic terminal, has been implicated in this process. Here we show that STEP(61) levels are progressively increased in the cortex of Tg2576 mice over the first year, as well as in prefrontal cortex of human AD brains.

Major vault protein is expressed along the nucleus-neurite axis and associates with mRNAs in cortical neurons.

Major Vault Protein (MVP), the main constituent of the vault ribonucleoprotein particle, is highly conserved in eukaryotic cells and upregulated in a variety of tumors. Vaults have been speculated to function as cargo transporters in several cell lines, yet no work to date has characterized the protein in neurons. Here we first describe the cellular and subcellular expression of MVP in primate and rodent cerebral cortex, and in cortical neurons in vitro.

A substrate trapping mutant form of striatal-enriched protein tyrosine phosphatase prevents amphetamine-induced stereotypies and long-term potentiation in the striatum.

Background: Chronic, intermittent exposure to psychostimulant drugs results in striatal neuroadaptations leading to an increase in an array of behavioral responses on subsequent challenge days. A brain-specific striatal-enriched tyrosine phosphatase (STEP) regulates synaptic strengthening by dephosphorylating and inactivating several key synaptic proteins. This study tests the hypothesis that a substrate-trapping form of STEP will prevent the development of amphetamine-induced stereotypies.

Knockout of striatal enriched protein tyrosine phosphatase in mice results in increased ERK1/2 phosphorylation.

STriatal Enriched protein tyrosine Phosphatase (STEP) is a brain-specific protein that is thought to play a role in synaptic plasticity. This hypothesis is based on previous findings demonstrating a role for STEP in the regulation of the extracellular signal-regulated kinase1/2 (ERK1/2). We have now generated a STEP knockout mouse and investigated the effect of knocking out STEP in the regulation of ERK1/2 activity.

The tyrosine phosphatase STEP mediates AMPA receptor endocytosis after metabotropic glutamate receptor stimulation.

Although it is well established that AMPA receptor (AMPAR) trafficking is a central event in several forms of synaptic plasticity, the mechanisms that regulate the surface expression of AMPARs are poorly understood. Previous work has shown that striatal-enriched protein tyrosine phosphatase (STEP) mediates NMDAR endocytosis. This protein tyrosine phosphatase is enriched in the synapses of the striatum, hippocampus, cerebral cortex, and other brain regions.

Translation of striatal-enriched protein tyrosine phosphatase (STEP) after beta1-adrenergic receptor stimulation.

The beta-adrenergic system is implicated in long-term synaptic plasticity in the CNS, a process that requires protein synthesis. To identify proteins that are translated in response to beta-adrenergic receptor stimulation and the pathways that regulate this process, we investigated the effects of isoproterenol on the translation of striatal-enriched protein tyrosine phosphatase (STEP) in both cortico-striatal slices and primary neuronal cultures. Isoproterenol stimulation induced a rapid dose-dependent increase in STEP expression.

Titin in insect spermatocyte spindle fibers associates with microtubules, actin, myosin and the matrix proteins skeletor, megator and chromator.

Titin, the giant elastic protein found in muscles, is present in spindles of crane-fly and locust spermatocytes as determined by immunofluorescence staining using three antibodies, each raised against a different, spatially separated fragment of Drosophila titin (D-titin). All three antibodies stained the Z-lines and other regions in insect myofibrils. In western blots of insect muscle extract the antibodies reacted with high molecular mass proteins, ranging between rat nebulin (600-900 kDa) and rat titin (3000-4000 kDa).

Molecular basis of genetic neuropsychiatric disorders.

The past decade has seen tremendous advances in our understanding of the molecular and genetic basis of many neuropsychiatric disorders. Although the genetic aberrations that lead to these syndromes have been identified in many cases, not much is known about specific gene products and their function. This article reviews the molecular basis of well-known neurogenetic disorders.

Mapping the Ca2+ -dependent binding of an invertebrate homolog of protein phosphatase 4 regulatory subunit 2 to the small EF-hand protein, calsensin.

The EF-hand family of calcium-binding proteins regulates cellular signal transduction events via calcium-dependent interactions with target proteins. Here, we show that the COOH-terminal tail of the leech homolog of protein phosphatase 4 regulatory subunit 2 (PP4-R2) interacts with the small neuronal EF-hand calcium-binding protein, Calsensin, in a calcium-dependent manner. Using two-dimensional NMR spectroscopy and chemical shift perturbations we have identified and mapped the residues of Calsensin that form a binding surface for PP4-R2.

Solution structure and backbone dynamics of Calsensin, an invertebrate neuronal calcium-binding protein.

Calsensin is an EF-hand calcium-binding protein expressed by a subset of peripheral sensory neurons that fasciculate into a single tract in the leech central nervous system. Calsensin is a 9-kD protein with two EF-hand calcium-binding motifs. Using multidimensional NMR spectroscopy we have determined the solution structure and backbone dynamics of calcium-bound Calsensin.

Leech filamin and Tractin: markers for muscle development and nerve formation.

The Lan3-14 and Laz10-1 monoclonal antibodies recognize a 400 kDa antigen that is specifically expressed by all muscle cells in leech. We show that the antigen recognized by both antibodies is a member of the filamin family of actin binding proteins. Leech filamin has two calponin homology domains and 35 filamin/ABP-repeat domains.