AMPAR exocytosis through NO modulation of PICK1.

The activation of NMDA receptors (NMDARs) triggers long-term changes in AMPA receptor-mediated synaptic transmission in the CNS. These long-lasting changes occur via the addition or removal of AMPA receptors (AMPARs) at the synaptic membrane and are mediated by a number of regulatory proteins including the GluR2 AMPAR-interacting proteins n-ethylmaleimide sensitive factor (NSF) and Protein Interacting with C Kinase (PICK1). We have shown that the potent activation of NMDARs drives unclustering of PICK1 and PICK1-GluR2 dissociation in dendrites resulting in increased surface delivery of AMPARs.

Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses.

Genetic deficiency of the mRNA binding protein FMRP results in the most common inherited form of mental retardation, Fragile X syndrome. We investigated the localization and function of FMRP during development of hippocampal neurons in culture. FMRP was distributed within granules that extended into developing axons and growth cones, detectable at distances over 300 microm from the cell body.

Localization of FMRP-associated mRNA granules and requirement of microtubules for activity-dependent trafficking in hippocampal neurons.

Fragile X syndrome is caused by the absence of the fragile X mental-retardation protein (FMRP), an mRNA-binding protein, which may play important roles in the regulation of dendritic mRNA localization and/or synaptic protein synthesis. We have recently applied high-resolution fluorescence imaging methods to document the presence, motility and activity-dependent regulation of FMRP granule trafficking in dendrites and spines of cultured hippocampal neurons. In this study, we show that FMRP granules distribute to F-actin-rich compartments, including filopodia, spines and growth cones during the staged development of hippocampal neurons in culture.

Localization of a beta-actin messenger ribonucleoprotein complex with zipcode-binding protein modulates the density of dendritic filopodia and filopodial synapses.

The dendritic transport and local translation of mRNA may be an essential mechanism to regulate synaptic growth and plasticity. We investigated the molecular mechanism and function of beta-actin mRNA localization in dendrites of cultured hippocampal neurons. Previous studies have shown that beta-actin mRNA localization to the leading edge of fibroblasts or the growth cones of developing neurites involved a specific interaction between a zipcode sequence in the 3' untranslated region and the mRNA-binding protein zipcode-binding protein-1 (ZBP1).

Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization.

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deletion and/or mutation of the survival motor neuron protein Gene (SMN1) that results in the expression of a truncated protein lacking the C terminal exon-7. Whereas SMN has been shown to be an important component of diverse ribonucleoprotein (RNP) complexes, its function in neurons is unknown. We hypothesize that the active transport of SMN may be important for neurite outgrowth and that disruption of exon-7 could impair its normal intracellular trafficking.

Sunrise at the synapse: the FMRP mRNP shaping the synaptic interface.

Recent studies provide new insight into the mechanistic function of Fragile X Mental Retardation Protein (FMRP), paving the way to understanding the biological basis of Fragile X Syndrome. While it has been known for several years that there are spine defects associated with the absence of the mRNA binding protein FMRP, it has been unclear how its absence may lead to specific synaptic defects that underlie the learning and cognitive impairments in Fragile X. One hypothesis under study is that FMRP may play a key role in the regulation of dendritically localized mRNAs, at subsynaptic sites where regulation of local protein synthesis may influence synaptic structure and plasticity.

Screening for Alzheimer's disease: the memory impairment screen versus the conventional three-word memory test.

Objectives: To improve screening for Alzheimer's disease (AD) with the Memory Impairment Screen (MIS), a 4-minute, four-item delayed free and cued recall memory test with controlled learning and high discriminative validity. To assess the discriminative validity of the MIS for AD and to compare it with the conventional three-word memory test, a delayed free recall task, widely recommended as a dementia-screening test in clinical practice.

Design: Cross-sectional validation study nested within a longitudinal study of aging and dementia.

Neurotrophin-induced transport of a beta-actin mRNP complex increases beta-actin levels and stimulates growth cone motility.

Neurotrophin regulation of actin-dependent changes in growth cone motility may depend on the signaling of beta-actin mRNA transport. Formation of an RNP complex between the beta-actin mRNA zipcode sequence and Zipcode Binding Protein 1 (ZBP1) was required for its localization to growth cones. Antisense oligonucleotides to the zipcode inhibited formation of this RNP complex in vitro and the neurotrophin-induced localization of beta-actin mRNA and ZBP1 granules.

How strong is the evidence for mediational hypotheses of age-related memory loss? Commentary.

Background: Luszcz and Bryan review research supporting three theories of age-related memory loss: the speed hypothesis, the executive function hypothesis, and the common cause hypothesis.

Objective: The aim of this commentary is to extend that review by encouraging consideration of the strength (or lack thereof) of the empirical evidence supporting theories of age-related memory loss.

Methods: Arguments are presented that call into the question the strength of the evidence that derives from cross-sectional analysis of individual difference sources of variance.

Cross-sectional and longitudinal relationships among age, cognition, and processing speed.

Cross-sectional and longitudinal age effects on cognitive function were examined in 302 older adults followed longitudinally. Processing speed was related to cognitive performance at cross-section, and change in speed predicted within-person longitudinal cognitive decline. Statistical control of processing speed greatly reduced cross-sectional age effects but did not attenuate longitudinal aging effects.

Screening for dementia with the memory impairment screen.

Objectives: To validate a sensitive and specific screening test for AD and other dementias, assess its reliability and discriminative validity, and present normative data for its use in various applied settings.

Background: To improve discrimination in screening for AD and dementia, we developed the Memory Impairment Screen (MIS), a 4-minute, four-item, delayed free- and cued-recall test of memory impairment. The MIS uses controlled learning to ensure attention, induce specific semantic processing, and optimize encoding specificity to improve detection of dementia.

Constraints on general slowing: a meta-analysis using hierarchical linear models with random coefficients.

General slowing (GS) theories are often tested by meta-analysis that model mean latencies of older adults as a function of mean latencies of younger adults. Ordinary least squares (OLS) regression is inappropriate for this purpose because it fails to account for the nested structure of multitask response time (RT) data. Hierarchical linear models (HLM) are an alternative method for analyzing such data.

Aging and counting speed: evidence for process-specific slowing.

The performance of adults ranging in age from 20 to 86 on two nonlexical tasks that required different types of counting operations was examined. Subproportional age effects for incrementing speed and for enumeration speed (counting 5 to 8 items) indicate that some types of counting processes are exempt from the slowing effects of aging. Increased age was associated with a diminished frequency and slowing of subitizing (counting < or = 4 items) as well as with slowing in the speed of initiating the incrementing process, but the course of age-related slowing for these measures is described by different functions.

Implicit and explicit memory in young, old, and demented adults.

Previous study of scopolamine and memory (Grober et al., 1989) showed that young adults given moderate or high doses of scopolamine maintained maximum cued recall in spite of a dose-dependent decrement in free recall when memory was assessed by cued selective reminding (CSR), a procedure which circumvents inattention and induces semantic processing. Intact recall by CSR indicates either that scopolamine impairs memory indirectly through effects on attention and information processing or that it impairs explicit memory but not implicit memory.

A prospective study of otitis media in infants born at very-low birthweight.

Forty-six infants born at very-low birthweight were followed prospectively for a one-year period after their discharge from a neonatal intensive care unit. Pneumatic otoscopy was used to diagnose otitis media at periodic visits to a medical/developmental follow-up program. Twenty-one normal, full-term infants routinely cared for in a well-baby nursery served as control subjects and were followed similarly for the same time period.