Showing papers by "Edward B. Ziff published in 2011"
TL;DR: Low-dose ketamine can treat depression-like behaviors induced by chronic neuropathic pain, and may be used to compliment sensory tests for assessment of pain in animal studies.
Abstract: Background
Chronic pain is associated with depression. In rodents, pain is often assessed by sensory hypersensitivity, which does not sufficiently measure affective responses. Low-dose ketamine has been used to treat both pain and depression, but it is not clear whether ketamine can relieve depression associated with chronic pain and whether this antidepressant effect depends on its anti-nociceptive properties.
157 citations
TL;DR: It is shown that visual deprivation (VD) increases extracellular serotonin in the juvenile rat barrel cortex, which facilitates synaptic strengthening at layer 4 to layer 2/3 synapses within the barrel cortex.
122 citations
TL;DR: It is suggested that activity-dependent substrate cleavage by synaptic metalloproteases and γ-secretase modifies synaptic transmission, providing a novel form of synaptic autoregulation.
Abstract: The proteolytic machinery comprising metalloproteases and γ-secretase, an intramembrane aspartyl protease involved in Alzheimer's disease, cleaves several substrates in addition to the extensively studied amyloid precursor protein. Some of these substrates, such as N-cadherin, are synaptic proteins involved in synapse remodeling and maintenance. Here we show, in rats and mice, that metalloproteases and γ-secretase are physiologic regulators of synapses. Both proteases are synaptic, with γ-secretase tethered at the synapse by δ-catenin, a synaptic scaffolding protein that also binds to N-cadherin and, through scaffolds, to AMPA receptor and a metalloprotease. Activity-dependent proteolysis by metalloproteases and γ-secretase takes place at both sides of the synapse, with the metalloprotease cleavage being NMDA receptor-dependent. This proteolysis decreases levels of synaptic proteins and diminishes synaptic transmission. Our results suggest that activity-dependent substrate cleavage by synaptic metalloproteases and γ-secretase modifies synaptic transmission, providing a novel form of synaptic autoregulation.
64 citations
TL;DR: It is demonstrated that cleaved ADAR2 leads to a decrease or loss of GluR2 editing, which will further result in high Ca2+ influx and excitotoxic neuronal death.
37 citations
TL;DR: A biochemical subcellular fractionation approach was used to determine whether brief intake of a 10% sucrose solution increases synaptic delivery of AMPA receptors in NAc of chronically food‐restricted (FR) relative to ad libitum fed (AL) rats, suggesting a promising new avenue to pursue in the effort to understand synaptic plasticity involved in adaptive and pathological food‐directed behavior and the mechanistic basis of severe dieting as a risk factor for the latter.
Abstract: Insertion and removal of AMPA receptors from the synaptic membrane underlie dynamic tuning of synaptic transmission and enduring changes in synaptic strength. Preclinical addiction research suggests that AMPA receptor trafficking plays an important role in nucleus accumbens (NAc) neuroplasticity underlying the compulsive and persistent quality of drug-seeking. Considering the parallels between drug addiction and compulsive eating, plus the supranormal reward properties of sucrose, and the role of dieting as a risk factor in development of binge pathology, the present study used a biochemical subcellular fractionation approach to determine whether brief intake of a 10% sucrose solution increases synaptic delivery of AMPA receptors in NAc of chronically food-restricted (FR) relative to ad libitum fed (AL) rats. FR, alone, produced a small but significant increase in synaptic expression of AMPA receptors. This may contribute to NAc integrative mechanisms that mediate the enhanced behavioral responsiveness of FR subjects to phasic reward stimuli, including food and drugs. Brief intake of sucrose increased GluR1 in the PSD, regardless of dietary condition, though the net effect was greater in FR than AL subjects. A marked increase in GluR2 was also observed, but only in FR rats. This set of results suggests that in FR subjects, sucrose may have primarily increased delivery of GluR1/GluR2 heteromers to the PSD, while in AL subjects sucrose increased delivery of GluR2-lacking channels. The functional consequences of these possible differences in subunit composition of trafficked AMPA receptors between diet groups remain to be determined. Nevertheless, the present set of results suggest a promising new avenue to pursue in the effort to understand synaptic plasticity involved in adaptive and pathological food-directed behavior and the mechanistic basis of severe dieting as a risk factor for the latter.
27 citations
TL;DR: A catalogue of candidate pathways involved in synaptic function that may be regulated by gamma-secretase is generated, including genes involved in Notch receptor signaling, cell-cell adhesion, and in synaptic transmission such as the NMDA NR2 receptor.
Abstract: Background: Gamma-secretase, which generates amyloid peptide from APP, also cleaves other type I transmembrane proteins, including synaptic proteins such as N-cadherin. The cleavage pathway involves initial ectodomain shedding by a metalloprotease, followed by intramembrane cleavage by gamma-secretase. The C-terminal fragments generated from the cleavage of several of gamma-secretase substrates can have signaling functions and can regulate transcription (Hass et al., 2009). We have previously shown the existence of activity-dependent cleavage of APP and N-cadherin bymetalloproteases and gamma-secretase at synapses. Moreover, these cleavages modify synaptic transmission and can thus provide a novel formof functional synaptic auto regulation. Methods: We thus assayed if gamma-secretase cleavage couldmodify gene regulation in neurons.We performed a microarray expression profiling analysis using RNA isolated from 14 DIV primary hippocampal neurons in culture treated with the gamma-secretase inhibitors, L685458 for 2h or 4h and compared them to untreated controls. The experiment was carried out in duplicate and the normalized array data were analyzed with the DAVID bioinformatic database and the Gene Set Enrichment Analysis (GSEA) tool. Results: Using the DAVID bioinformatic database, we observed a down regulation of genes involved in Notch receptor signaling, including HES1, as expected. Moreover, we found that apoptosis and Wnt signaling programs were remodeled based on both up regulated and down regulated genes. Interestingly a number of genes coding for potassium channels, adhesionmolecules and synaptic proteinswere down regulated. Analogously, using GSEA, we identified down regulation of genes involved in theNotch receptor signaling, aswell as others involved in cell-cell adhesion, such asE-cadherin, and in synaptic transmission such as theNMDA NR2 receptor. Interestingly we also observed a down regulation of MT5MMP gene, a metalloprotease involved in N-cadherin cleavage in neurons, and of Presenilin1, one of the components of gamma-secretase.Conclusions: In conclusion, we generated a catalogue of candidate pathways involved in synaptic function that may be regulated by gamma-secretase. Reference: [1] Hass MR, Sato C, Kopan R, Zhao G (2009) Presenilin:RIP and beyond. Seminars in Cell & Developmental Biology 20:201-210.