Reelin Mobilizes a VAMP7-Dependent Synaptic Vesicle Pool and Selectively Augments Spontaneous Neurotransmission

SummaryReelin is a glycoprotein that is critical for proper layering of neocortex during development as well as dynamic regulation of glutamatergic postsynaptic signaling in mature synapses. Here, we show that Reelin also acts presynaptically, resulting in robust rapid enhancement of spontaneous neurotransmitter release without affecting properties of evoked neurotransmission. This effect of Reelin requires a modest but significant increase in presynaptic Ca2+ initiated via ApoER2 signaling. The specificity of Reelin action on spontaneous neurotransmitter release is encoded at the level of vesicular SNARE machinery as it requires VAMP7 and SNAP-25 but not synaptobrevin2, VAMP4, or vti1a. These results uncover a presynaptic regulatory pathway that utilizes the heterogeneity of synaptic vesicle-associated SNAREs and selectively augments action potential-independent neurotransmission

Leptin Replacement Improves Cognitive Development

Leptin changes brain structure, neuron excitability and synaptic plasticity. It also regulates the development and function of feeding circuits. However, the effects of leptin on neurocognitive development are unknown.To evaluate the effect of leptin on neurocognitive development.A 5-year-old boy with a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) was treated with recombinant methionyl human leptin (r-metHuLeptin) at physiologic replacement doses of 0.03 mg/kg/day. Cognitive development was assessed using the Differential Ability Scales (DAS), a measure of general verbal and nonverbal functioning; and selected subtests from the NEPSY, a measure of neuropsychological functioning in children.Prior to treatment, the patient was morbidly obese, hypertensive, dyslipidemic, and hyperinsulinemic. Baseline neurocognitive tests revealed slower than expected rates of development (developmental age lower than chronological age) in a majority of the areas assessed. After two years, substantial increases in the rates of development in most neurocognitive domains were apparent, with some skills at or exceeding expectations based on chronological age. We also observed marked weight loss and resolution of hypertension, dyslipidemia and hyperinsulinemia.We concluded that replacement with r-metHuLeptin is associated with weight loss and changes in rates of development in many neurocognitive domains, which lends support to the hypothesis that, in addition to its role in metabolism, leptin may have a cognitive enhancing role in the developing central nervous system.ClinicalTrials.gov NCT00659828

Identification of Stk25 as a genetic modifier of Tau phosphorylation in Dab1-mutant mice.

Hyperphosphorylation of the microtubule binding protein Tau is a feature of a number of neurodegenerative diseases, including Alzheimer's disease. Tau is hyperphosphorylated in the hippocampus of dab1-null mice in a strain-dependent manner; however, it has not been clear if the Tau phosphorylation phenotype is a secondary effect of the morbidity of these mutants. The dab1 gene encodes a docking protein that is required for normal brain lamination and dendritogenesis as part of the Reelin signaling pathway. We show that dab1 gene inactivation after brain development leads to Tau hyperphosphorylation in anatomically normal mice. Genomic regions that regulate the phospho Tau phenotype in dab1 mutants have previously been identified. Using a microarray gene expression comparison between dab1-mutants from the high-phospho Tau expressing and low-phospho Tau expressing strains, we identified Stk25 as a differentially expressed modifier of dab1-mutant phenotypes. Stk25 knockdown reduces Tau phosphorylation in embryonic neurons. Furthermore, Stk25 regulates neuronal polarization and Golgi morphology in an antagonistic manner to Dab1. This work provides insights into the complex regulation of neuronal behavior during brain development and provides insights into the molecular cascades that regulate Tau phosphorylation

Relationship between leukocyte and subtype counts, low-grade inflammation and slow coronary flow phenomenon in patients with angiographically normal coronary arteries

Background: Slow coronary flow (SCF) is an angiographic finding characterized by delayed opacification of epicardial coronary arteries in the absence of obstructive coronary disease. Leukocytes and low-grade inflammation play a major role in atherosclerotic vascular processes and may be important in other coronary pathologies. Therefore, we aimed to investigate whether there is a positive correlation between leukocyte counts, high-sensitive C-reactive protein (hsCRP) and SCF determined by frame rates. Methods: Seventy-seven individuals who underwent coronary angiography with suspected CAD, and had angiographically normal coronary arteries (NCA) of varying coronary flow rates were enrolled. From the original 77 study participants, forty-seven patients with NCA and SCF in all three coronary vessels and 30 sex- and age-matched control participants with NCA but without SCF were investigated. The quantification of the coronary flow was assessed by use of the TIMI frame count method (TFC) in all coronary arteries. The normal flow was defined as TFC < 28 frames and slow flow as TFC ? 28 frames. Results: HsCRP was significantly positively correlated with mean TFC (r = 0.522, p < 0.001). In addition, leukocytes, neutrophils and monocytes were significantly positively related to mean TFC (r = 0.353, p = 0.002; r = 0.298, p = 0.009 and r = 0.511, p < 0.001, respectively). In multivariate analyses, only hsCRP (?: 0.324, p = 0.003) and monocyte count (?: 0.354, p = 0.003) were related to SCF as determined by TFC. Conclusion: Our results showed that circulating monocytes and low-grade inflammation are related to SCF. Although we cannot make conclusive assumptions about the underlying pathologic process of SCF, we believe that these findings may be pivotal for further studies which seek to ascertain the specific roles of monocytes and hsCRP on SCF phenomenon in coronary vasculature

Increased pulse wave velocity in patients with panic disorder: Independent vascular influence of panic disorder on arterial stiffness

PubMed: 22789419Objective: Acute and chronic mental stress and many psychiatric disorders have been accepted as a cause of cardiovascular disease. Panic disorder, a subtype of anxiety disorder, has been associated with increased risk of fatal myocardial infarction and sudden cardiac death in epidemiological studies. Carotid-femoral pulse wave velocity (CF-PWV) is currently the gold standard measurement of arterial stiffness. CF-PWV is a well-recognized predictor of an adverse cardiovascular outcome with higher predictive value than classical cardiovascular risk factors. The aim of our study is to measure PWV as the surrogate of arterial stiffness and vascular involvement in patients with panic disorder. Methods: Forty-two patients with PD, and 30 control participants were included in the study. Patients with hypertension, diabetes mellitus, or the history of any cardiovascular disease were excluded from study. Results: Baseline characteristics were not significantly different between the two groups, except carotid-femoral pulse wave velocity (PD vs. control; 7.51 ± 2.02 vs. 6.24 ± 1.09. m/s, p=0.001), heart rate, and smoking status. Additionally, CF-PWV positively correlated with age (r=0.250, p=0.034), heart rate (r=0.284, p=0.017), systolic and diastolic blood pressure (r=0.393, p=0.001 and r=0.286, p=0.015, respectively) significantly. However, only the presence of panic disorder was independently related to PWV (?eta: 0.317, p=0.011) in the multivariate analysis including age, heart rate, smoking status and blood pressure measurements. Conclusion: Increased pulse wave velocity in patients with panic disorder may justify the associated risk as documented in previous studies, and may be useful in identifying the patients with higher risk of future cardiovascular complications. © 2012 Elsevier Inc

INCREASED CIRCULATING SOLUBLE CD40 LEVELS IN PATIENTS WITH SLOW CORONARY FLOW PHENOMENON

WOS: 000317946500063[No abstract available