Profound impairment in social interaction is a core symptom of autism, a severe neurodevelopmental disorder. Deficits can include a lack of interest in social contact and low levels of approach and proximity to other children. In this study, a three-chambered choice task was used to evaluate sociability and social novelty preference in five lines of mice with mutations in genes implicated in autism spectrum disorders. Fmr1 tm1Cgr/Y (Fmr1 À/y ) mice represent a model for fragile X, a mental retardation syndrome that is partially comorbid with autism. We tested Fmr1 À/y mice on two genetic backgrounds, C57BL/6J and FVB/N-129/OlaHsd (FVB/129). Targeted disruption of Fmr1 resulted in low sociability on one measure, but only when the mutation was expressed on FVB/129. Autism has been associated with altered serotonin levels and polymorphisms in SLC6A4 (SERT), the serotonin transporter gene. Male mice with targeted disruption of Slc6a4 displayed significantly less sociability than wild-type controls. Mice with conditional overexpression of Igf-1 (insulin-like growth factor-1) offered a model for brain overgrowth associated with autism. Igf-1 transgenic mice engaged in levels of social approach similar to wild-type controls. Targeted disruption in other genes of interest, En2 (engrailed-2) and Dhcr7, was carried on genetic backgrounds that showed low levels of exploration in the choice task, precluding meaningful interpretations of social behavior scores. Overall, results show that loss of Fmr1 or Slc6a4 gene function can lead to deficits in sociability. Findings from the fragile X model suggest that the FVB/129 background confers enhanced susceptibility to consequences of Fmr1 mutation on social approach.
Background and Purpose-Thrombectomy, primarily with stent retrievers with or without adjunctive aspiration, provided clinical benefit across multiple prospective randomized trials. Whether this benefit is exclusive to stent retrievers is unclear. Methods-THERAPY (The Randomized, Concurrent Controlled Trial to Assess the Penumbra System's Safety and Effectiveness in the Treatment of Acute Stroke; NCT01429350) was an international, multicenter, prospective, randomized (1:1), open label, blinded end point evaluation, concurrent controlled clinical trial of aspiration thrombectomy after intravenous alteplase (IAT) administration compared with intravenous-alteplase alone in patients with large vessel ischemic stroke because of a thrombus length of ≥8 mm. The primary efficacy end point was the percent of patients achieving independence at 90 days (modified Rankin Scale score, 0-2; intention-to-treat analysis). The primary safety end point was the rate of severe adverse events (SAEs) by 90 days (as treated analysis). Patients were randomized 1:1 across 36 centers in 2 countries (United States and Germany). Results-Enrollment was halted after 108 (55 IAT and 53 intravenous) patients (of 692 planned) because of external evidence of the added benefit of endovascular therapy to intravenous-alteplase alone. Functional independence was achieved in 38% IAT and 30% intravenous intention-to-treat groups (P=0.52). Intention-to-treat ordinal modified Rankin Scale odds ratio was 1.76 (95% confidence interval, 0.86-3.59; P=0.12) in favor of IAT. Secondary efficacy analyses all demonstrated a consistent direction of effect toward benefit of IAT. No differences in symptomatic intracranial hemorrhage rates (9.3% IAT versus 9.7% intravenous, P=1.0) or 90-day mortality (IAT: 12% versus intravenous: 23.9%, P=0.18) were observed. Conclusions-THERAPY did not achieve its primary end point in this underpowered sample. Directions of effect for all prespecified outcomes were both internally and externally consistent toward benefit. It is possible that an alternate method of thrombectomy, primary aspiration, will benefit selected patients harboring large vessel occlusions. Further study on this topic is indicated. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01429350.
Fragile X mental retardation is caused by absence of the RNAbinding protein fragile X mental retardation protein (FMRP), encoded by the FMR1 gene. There is increasing evidence that FMRP regulates transport and modulates translation of some mRNAs. We studied neurotransmitter-activated synaptic protein synthesis in fmr1-knockout mice. Synaptoneurosomes from knockout mice did not manifest accelerated polyribosome assembly or protein synthesis as it occurs in wild-type mice upon stimulation of group I metabotropic glutamate receptors. Direct activation of protein kinase C did not compensate in the knockout mouse, indicating that the FMRP-dependent step is further along the signaling pathway. Visual cortices of young knockout mice exhibited a lower proportion of dendritic spine synapses containing polyribosomes than did the cortices of wild-type mice, corroborating this finding in vivo. This deficit in rapid neurotransmitter-controlled local translation of specific proteins may contribute to morphological and functional abnormalities observed in patients with fragile X syndrome.dendrites ͉ metabotropic glutamate receptor ͉ mRNA ͉ plasticity ͉ ultrastructure F ragile X mental retardation syndrome is an inherited, Xlinked disorder. In most patients, methylation of an extreme expansion (200-1,000 repeats) of a (CGG)n trinucleotide repeat in the 5Ј UTR of the FMR1 gene blocks transcription of fmr1 mRNA (1). The resulting absence of fragile X mental retardation protein (FMRP) causes the syndrome, which is characterized by mental retardation, macroorchidism, and behavioral abnormalities (2). The brains of these patients exhibit an unusual, spindly appearance of the dendritic spines as well as an overabundance of spines (3, 4), a morphology that resembles early postnatal tissue.The function of FMRP is unknown; in neurons much of the protein is found in dendrites (5). FMRP contains RNA-binding elements (6) and is associated with actively translating polyribosomes in the brain (7-9). Several laboratories have described sets of mRNAs bound by FMRP (10-12), and specific motifs involved in FMRP binding of some mRNAs have been identified (13,14). Recently, we demonstrated (10) that several members of a subset of mRNAs bound by FMRP in intact cells are differentially distributed and͞or translated in dendritic, as compared to somatic, subcellular domains. This finding suggests direct involvement of FMRP in transport and͞or translation of mRNA in dendrites. Antar et al. (15) have demonstrated rapid transport of FMRP into dendrites upon KCl depolarization. We report here that a dynamic aspect of translation, neurotransmitter-induced rapid initiation, is directly impacted by the absence of FMRP.Protein translation in dendrites was suggested by early descriptions of postsynaptic polyribosomal aggregates (PRAs) during synaptogenesis and in the visual cortex of rats reared in complex environments, indicating the importance of local translation for synaptic plasticity (16,17). Components necessary for translation are present postsynaptic...
These results indicate that abnormal dendritic outgrowth or maintenance contributes to reduced neuropil and prefrontal connectivity in schizophrenia. Short postmortem intervals and resulting high tissue quality suggest that these dystrophic changes reflect schizophrenia pathology rather than postmortem artifact.
Recent positive trials have thrust acute cerebral perfusion imaging into the routine evaluation of acute ischemic stroke. Updated guidelines state that in patients with anterior circulation large vessel occlusions presenting beyond 6 hours from time last known well, advanced imaging selection including perfusion-based selection is necessary. Centers that receive patients with acute stroke must now have the capability to perform and interpret CT or magnetic resonance perfusion imaging or provide rapid transfer to centers with the capability of selecting patients for a highly impactful endovascular therapy, particularly in delayed time windows. Many stroke centers are quickly incorporating the use of automated perfusion processing software to interpret perfusion raw data. As CT perfusion (CTP) is being assimilated in real-world clinical practice, it is essential to understand the basics of perfusion acquisition, quantification, and interpretation. It is equally important to recognize the common technical and clinical diagnostic challenges of automated CTP including ischemic core and penumbral misclassifications that could result in underestimation or overestimation of the core and penumbra volumes. This review highlights the pitfalls of automated CTP along with practical pearls to address the common challenges. This is particularly tailored to aid the acute stroke clinician who must interpret automated perfusion studies in an emergency setting to make time-dependent treatment decisions for patients with acute ischemic stroke.
Behavioral experiences can modulate neural networks through changes in synaptic morphology and number. In contrast, abnormal morphogenesis of dendritic spines is associated with cognitive impairment, as in Fragile X syndrome. Dendritic or synaptic protein synthesis could provide the specificity and speed necessary for spine morphogenesis. Here, we highlight locally translated proteins shown to affect synaptic morphology (e.g., Fragile X mental retardation protein).
Fragile X syndrome (FXS) is the most common form of inherited mental retardation. Observed neuropathologies associated with FXS include abnormal length, morphology, and density of dendritic spines, reported in individuals with FXS and in Fmr1 knockout (KO) mice, an animal model of FXS. To date, however, these neuropathologies have been studied in Fmr1 KO mice bred in a FVB background (a strain with genetic mutations that complicate interpretation of results) and findings have been inconsistent. Here, Golgi-Cox impregnation was used to investigate length, morphology, and density of dendritic spines on layer V pyramidal neurons in visual cortices of Fmr1 KO and wildtype (WT) mice bred in a C57BL/6 background. We report that spine abnormalities in these animals parallel abnormalities reported in humans with FXS, perhaps to a greater degree than KO mice bred in an FVB background. Specifically, Fmr1 KO mice bred in a C57BL/6 background exhibited significantly more longer dendritic spines and fewer shorter spines, as well as more spines with immature-appearing morphology and fewer with mature-appearing morphology than WT littermates. Spine length abnormalities were demonstrated to be largely independent of spine morphology abnormalities, as the length phenotype was observed in KOs even within a morphological category. Fmr1 KO mice also had a greater overall spine density than WTs. These findings provide powerful support for the essence of the dendritic spine abnormalities in the absence of FMRP, now found to be largely consistent with human data across two mouse backgrounds.
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