Defective synapse maturation and enhanced synaptic plasticity in Shank2 Δex7(-/-) mice

Autism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic etiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are used for a mechanistic understanding of ASDs and the development of therapeutic strategies. SHANKs are scaffold proteins in the postsynaptic density of mammalian excitatory synapses with proposed functions in synaptogenesis, regulation of dendritic spine morphology, and instruction of structural synaptic plasticity. In contrast to all studies so far on the function of SHANK proteins, we have previously observed enhanced synaptic plasticity in Shank2 Δex7(-/-) mice. In a series of experiments, we now reproduce these results, further explore the synaptic phenotype, and directly compare our model to the independently generated Shank2 Δex6-7(-/-) mice. Minimal stimulation experiments reveal that Shank2 Δex7(-/-) mice possess an excessive fraction of silent (i.e., α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, short, AMPA receptor lacking) synapses. The synaptic maturation deficit emerges during the third postnatal week and constitutes a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation, both in vivo and in vitro. A direct comparison with Shank2 Δex6-7(-/-) mice adds weight to the hypothesis that both mouse models show a different set of synaptic phenotypes, possibly due to differences in their genetic background. These findings add to the diversity of synaptic phenotypes in neurodevelopmental disorders and further support the supposed existence of "modifier genes" in the expression and inheritance of ASDs

Defective Synapse Maturation and Enhanced Synaptic Plasticity in Shank2 Δex7-/- Mice

Autism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic etiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are used for a mechanistic understanding of ASDs and the development of therapeutic strategies. SHANKs are scaffold proteins in the postsynaptic density of mammalian excitatory synapses with proposed functions in synaptogenesis, regulation of dendritic spine morphology, and instruction of structural synaptic plasticity. In contrast to all studies so far on the function of SHANK proteins, we have previously observed enhanced synaptic plasticity in Shank2 Δex7-/- mice. In a series of experiments, we now reproduce these results, further explore the synaptic phenotype, and directly compare our model to the independently generated Shank2 Δex6-7-/- mice. Minimal stimulation experiments reveal that Shank2 Δex7-/- mice possess an excessive fraction of silent (i.e., α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, short, AMPA receptor lacking) synapses. The synaptic maturation deficit emerges during the third postnatal week and constitutes a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation, both in vivo and in vitro. A direct comparison with Shank2 Δex6-7-/- mice adds weight to the hypothesis that both mouse models show a different set of synaptic phenotypes, possibly due to differences in their genetic background. These findings add to the diversity of synaptic phenotypes in neurodevelopmental disorders and further support the supposed existence of "modifier genes" in the expression and inheritance of ASDs

Effect of Fish Oil on Ventricular Tachyarrhythmia and Death in Patients With Implantable Cardioverter Defibrillators: The Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) Randomized Trial

Context Very-long-chain n-3 polyunsaturated fatty acids (omega-3 PUFAs) from fish are thought to reduce risk of sudden death, possibly by reducing susceptibility to cardiac arrhythmia. Objective To study the effect of supplemental fish oil vs placebo on ventricular tachyarrhythmia or death. Design, Setting, and Patients The Study on Omega-3 Fatty acids and ventricular Arrhythmia ( SOFA) was a randomized, parallel, placebo-controlled, double-blind trial conducted at 26 cardiology clinics across Europe. A total of 546 patients with implantable cardioverter-defibrillators ( ICDs) and prior documented malignant ventricular tachycardia ( VT) or ventricular fibrillation ( VF) were enrolled between October 2001 and August 2004. Patients were randomly assigned to receive 2 g/d of fish oil ( n= 273) or placebo ( n= 273) for a median period of 356 days ( range, 14-379 days). Main Outcome Measure Appropriate ICD intervention for VT or VF, or all-cause death. Results The primary end point occurred in 81 ( 30%) patients taking fish oil vs 90 ( 33%) patients taking placebo ( hazard ratio [ HR], 0.86;95% confidence interval [ CI], 0.64-1.16; P=. 33). In prespecified subgroup analyses, the HR was 0.91 ( 95% CI, 0.661.26) for fish oil vs placebo in the 411 patients who had experienced VT in the year before the study, and 0.76 ( 95% CI, 0.52-1.11) for 332 patients with prior myocardial infarctions. Conclusion Our findings do not indicate evidence of a strong protective effect of intake of omega-3 PUFAs from fish oil against ventricular arrhythmia in patients with ICDs