Interneuron Simplification and Loss of Structural Plasticity As Markers of Aging-Related Functional Decline

Changes in excitatory neuron and synapse structure have been recognized as a potential physical source of age-related cognitive decline. Despite the importance of inhibition to brain plasticity, little is known regarding aging-associated changes to inhibitory neurons. Here we test for age-related cellular and circuit changes to inhibitory neurons of mouse visual cortex. We find no substantial difference in inhibitory neuron number, inhibitory neuronal subtypes, or synapse numbers within the cerebral cortex of aged mice compared with younger adults. However, when comparing cortical interneuron morphological parameters, we find differences in complexity, suggesting that arbors are simplified in aged mice. In vivo two-photon microscopy has previously shown that in contrast to pyramidal neurons, inhibitory interneurons retain a capacity for dendritic remodeling in the adult. We find that this capacity diminishes with age and is accompanied by a shift in dynamics from balanced branch additions and retractions to progressive prevalence of retractions, culminat-ingina dendritic arbor that is both simpler and more stable. Recording of visually evoked potentials shows that aging-related interneuron dendritic arbor simplification and reduced dynamics go hand in hand with loss of induced stimulus-selective response potentiation (SRP), a paradigm for adult visual cortical plasticity. Chronic treatment with the antidepressant fluoxetine reversed deficits in interneuron structural dynamics and restored SRP in aged animals. Our results support a structural basis for age-related impairments in sensory perception, and suggest that declines in inhibitory neuron structural plasticity during aging contribute to reduced functional plasticity.National Eye Institute (Grants RO1EY01756, RO1EY025437 and RO1EY023037)NINDS (Grant K99-NS076364

CPG15 regulates synapse stability in the developing and adult brain

Development of the CNS involves a phase in which neural circuits are refined based on use and experience. This occurs by selective stabilization of specific neuronal connections and is guided by neural activity patterns. Nedivi and colleagues now describe a role for CPG15 in regulating this process. They characterize the very first cgp15 knockout (cpg15 KO) mouse using a multidisciplinary approach that includes electrophysiology, electron microscopy, live in vivo cortical imaging, and behavioral analysis. cpg15 KO mice display developmental delays in the formation of excitatory synapses and gradual spine loss, leading to poor learning ability. CPG15 is shown to have a key role in stabilizing active synapses on dendritic spines

Genomic Divergence among Sindbis Virus Strains

Antigenic variants of the alphavirus Sindbis strains have been isolated from the Paleartic, Ethiopian, Oriental, and Australian zoogeographic regions. The genome of these variants were analyzed for homology by hybridization of virion RNAs to double-stranded RNAs isolated from infected cells. Under nonstringent conditions (Tm-55°) the RNA of Oriental-Australian strains showed only 35 to 51% nucleotide sequence homology with the RNAs of the Paleartic-Ethiopian strains although homology was essentially complete among isolates within the Oriental and Australian regions and among isolates within the Paleartic and Ethiopian regions. Under more stringent conditions (Tm-26°), nucleotide sequence differences of 2 to 45% were detected among the RNAs of virus strains from geographically distant localities within each of these two major zoogeographic subdivisions. Year of isolation, passage histoty and vertebrate or invertebrate host of origin were not major determinants of sequence heterology. The hypothesis that ancestral Sindbis virus became separated by geographic barriers and evolved into two distinct types is presented. Further divergent evolution has obviously occurred wihin each of these types

Reversible modulations of neuronal plasticity by VEGF

Neurons, astrocytes, and blood vessels are organized in functional “neurovascular units” in which the vasculature can impact neuronal activity and, in turn, dynamically adjust to its change. Here we explored different mechanisms by which VEGF, a pleiotropic factor known to possess multiple activities vis-à-vis blood vessels and neurons, may affect adult neurogenesis and cognition. Conditional transgenic systems were used to reversibly overexpress VEGF or block endogenous VEGF in the hippocampus of adult mice. Importantly, this was done in settings that allowed the uncoupling of VEGF-promoted angiogenesis, neurogenesis, and memory. VEGF overexpression was found to augment all three processes, whereas VEGF blockade impaired memory without reducing hippocampal perfusion or neurogenesis. Pertinent to the general debate regarding the relative contribution of adult neurogenesis to memory, we found that memory gain by VEGF overexpression and memory impairment by VEGF blockade were already evident at early time points at which newly added neurons could not yet have become functional. Surprisingly, VEGF induction markedly increased in vivo long-term potentiation (LTP) responses in the dentate gyrus, and VEGF blockade completely abrogated LTP. Switching off ectopic VEGF production resulted in a return to a normal memory and LTP, indicating that ongoing VEGF is required to maintain increased plasticity. In summary, the study not only uncovered a surprising role for VEGF in neuronal plasticity, but also suggests that improved memory by VEGF is primarily a result of increasing plasticity of mature neurons rather than the contribution of newly added hippocampal neurons

Improving the Stability and Activity of Oral Therapeutic Enzymes—Recent Advances and Perspectives

Exogenous, orally-administered enzymes are currently in clinical use or under development for the treatment of pathologies, such as celiac disease and phenylketonuria. However, the administration of therapeutic enzymes via the oral route remains challenging due to potential inactivation of these fragile macromolecular entities in the harsh environment of the gastrointestinal tract. Enzymes are particularly sensitive because both proteolysis and unfolding can lead to their inactivation. Current efforts to overcome these shortcomings involve the application of gastro-resistant delivery systems and the modification of enzyme structures by polymer conjugation or protein engineering. This perspective manuscript reviews and critically discusses recent progress in the oral delivery of therapeutic enzymes, whose substrate is localized in the gastrointestinal tract.ISSN:0724-8741ISSN:1573-904

Structural aspects of therapeutic enzymes to treat metabolic disorders

10.1002/humu.21111Human Mutation30121591-1610HUMU