Contributions of metabotropic glutamate receptors to the pathophysiology of autism

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2013.Cataloged from PDF version of thesis. Vita.Includes bibliographical references (p. 153-184).Autism spectrum disorder (ASD) is a complex and heterogeneous disorder, and in the vast majority of cases the etiology is unknown. However, there are many syndromes of known genetic origin that have a high incidence of autism. These highly penetrant syndromic forms of autism offer a unique opportunity for the study of ASD because animal models can be readily engineered to carry the same genetic disruption. Animal models are crucial for understanding neurological disorders at the biological level, and while these monogenic disorders are relatively rare, their animal models are likely to prove indispensable in identifying common pathogenic pathways in ASD and associated intellectual disability (ID). As evidence accumulates from genetic and molecular studies, autism is increasingly being regarded as a disease of the synapse. In particular, a preponderance of genes associated with ASD appear to regulate the synaptic signaling pathways necessary for the proper control of neuronal protein synthesis. Here, we test the hypothesis that many ASDs may result from alterations in synaptic protein synthesis by examining neuronal translation in the mouse models of fragile X (FX) and tuberous sclerosis (TSC), the two leading inherited causes of ASD. Specifically, we determined if altered synaptic protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5) is a shared disruption in these disorders, and therefore may ultimately contribute to the pathophysiology of ASD in general. First, we show that multiple aspects of mGluR-mediated protein synthesis are altered in the mouse model of FX, suggesting that exaggeration of these processes may account for the diverse phenotypes associated with the disorder. Next, we demonstrate that disruptions in the mGluR pathway do not appear to be limited to this FX, as there is diminished synaptic protein synthesis and mGluR-LTD in a mouse model of TSC as well. This suggests that genetically heterogeneous causes of ASD and ID may produce similar deficits through bidirectional deviations in mGluR-mediated protein synthesis. Finally, we address the mechanisms by which mGluR activation is coupled to protein synthesis, which may elucidate novel avenues for the next generation of mGluR-based therapies for the treatment of ASD.by Benjamin D. Auerbach.Ph.D

Insulin signaling regulates neurite growth during ecdysone-dependent neuronal remodeling

The morphological rearrangement of neurons to accommodate new functions or activities is called "neuronal remodeling". Although neuronal remodeling is an important feature of nervous systems, the mechanisms governing the transition of neurons, from relatively stable states to more dynamic and differentiative remodeling states, are largely unknown. In holometabolous insects, there is a major transition from maintenance growth to organizational growth near the onset of metamorphosis, and these changes provide an unparalleled opportunity to explore the underlying mechanisms of neuronal remodeling. Many differentiated larval neurons are maintained throughout metamorphosis and undergo extensive remodeling, which involves the elimination of larval dendrites and axons (neurites) and the outgrowth and elaboration of adult-specific projections (Levine and Truman 1982; Brown, Cherbas et al. 2006). Here, I show that a metamorphosis-specific increase in insulin and insulin-like-growth factor signaling (IIS) promotes neuronal growth and axon branching after a long period of morphological stability during the larval stages. In a previous gain-of-function genetic screen, we found that overexpression of a negative effector in the IIS pathway, Forkhead box, sub-group O (FOXO), blocked the metamorphic growth of peptidergic neurons that secrete crustacean cardioactive peptide (CCAP) and bursicon. RNA interference (RNAi) and CCAP/bursicon cell-targeted expression of dominant negative constructs for other components of the IIS pathway [Insulin-like receptor (InR), Pi3K92E, Akt1, and S6K] also partially suppressed the growth of the CCAP/bursicon neuron somata and neurite arborization. In contrast, expression of wild-type or constitutively active forms of InR, Pi3K92E, Akt1, Rheb, and Target of rapamycin (TOR), as well as RNAi for negative regulators of the IIS pathway (PTEN and FOXO), stimulated overgrowth. Interestingly, InR displayed little effect on larval growth of the CCAP/bursicon neurons, but strong effects on the metamorphic outgrowth of these neurons. In addition, manipulations of IIS in a pan-peptidergic neuronal pattern revealed a general role in promoting organizational outgrowth of many neurons during metamorphosis. These results reveal that specific activation of IIS during metamorphosis facilitates renewed organizational growth in mature neurons. In order to further elucidate the molecular and cellular mechanisms governing IIS regulation of the metamorphic remodeling, I performed a genetic modifier screen to detect IIS-interacting genes. I screened 492 deficiency lines for modifiers of a foxo overexpression phenotype (wing expansion defects). A total of 14 deficiencies were confirmed as suppressors of foxo, and 19 were confirmed as enhancers. Two selected suppressors, Df(1)Exel6221 and Df(1)Exel6002, strongly reversed the effects of foxo on neuronal outgrowth. Df(1)Exel6221 also significantly rescued the phenotypes produced by expression of InRDN, suggesting that the gene(s) within Df(1)ExEL6221 might be involved in IIS-mediated growth during the neuronal remodeling process. The source of suppression in Df(1)Exel6002 was mapped to an individual locus, Su(z)2. Reduced expression of Su(z)2 by RNAi suppressed the effects of FOXO on neuronal outgrowth. Su(z)2 is a Zinc finger protein that belongs to the Drosophila Polycomb Group (PcG) protein family, the members of which function as negative regulators of transcription and chromatin modification (Brunk, Martin et al. 1991). This indicates that transcriptional regulation through chromatin modification by Su(z)2 may play an important role in reprogramming neuronal entry into the organizational growth phase, or in the execution of that growth program

Hippocampal gabaergic inhibitory interneurons

This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this record In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10–15% of the total neuronal population; however, their remarkable anatomical and physiological diversity allows them to regulate virtually all aspects of cellular and circuit function. Here we provide an overview of the current state of the field of interneuron research, focusing largely on the hippocampus. We discuss recent advances related to the various cell types, including their development and maturation, expression of subtype-specific voltage-and ligand-gated channels, and their roles in network oscillations. We also discuss recent technological advances and approaches that have permitted high-resolution, subtype-specific examination of their roles in numerous neural circuit disorders and the emerging therapeutic strategies to ameliorate such pathophysiological conditions. The ultimate goal of this review is not only to provide a touchstone for the current state of the field, but to help pave the way for future research by highlighting where gaps in our knowledge exist and how a complete appreciation of their roles will aid in future therapeutic strategies.National Institute of Child Health and Human Developmen

Hippocampal GABAergic inhibitory interneurons

In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10–15% of the total neuronal population; however, their remarkable anatomical and physiological diversity allows them to regulate virtually all aspects of cellular and circuit function. Here we provide an overview of the current state of the field of interneuron research, focusing largely on the hippocampus. We discuss recent advances related to the various cell types, including their development and maturation, expression of subtype-specific voltage- and ligand-gated channels, and their roles in network oscillations. We also discuss recent technological advances and approaches that have permitted high-resolution, subtype-specific examination of their roles in numerous neural circuit disorders and the emerging therapeutic strategies to ameliorate such pathophysiological conditions. The ultimate goal of this review is not only to provide a touchstone for the current state of the field, but to help pave the way for future research by highlighting where gaps in our knowledge exist and how a complete appreciation of their roles will aid in future therapeutic strategies

Clear Cell Renal Cell Carcinoma 2021–2022

Clear cell renal cell carcinoma is currently one of the most interesting areas of study in oncology. Despite the advances made in this field, this tumor continues to be a health problem of major concern in Western societies, seriously affecting public health services. Several characteristics of this tumor make it an exciting meeting point for translational collaboration between clinicians and basic researchers. Clear cell renal cell carcinoma is a paradigmatic example of inter- and intra-tumor heterogeneity from morphological, immunohistochemical, and molecular viewpoints. This tumor is also a good example to investigate the complexity of tumor/tumor and tumor/environment relationships from an ecological perspective. A deeper identification of the varied internal tumor self-organization through the specialization of cell clones and subclones as local invaders and metastasizers, on one hand, and the interactions of specific subsets of tumor cells with the local host microenvironment, on the other, will significantly enrich our knowledge of this neoplasm. Clear cell renal cell carcinoma is also a paradigmatic test bench for antiangiogenic and immune checkpoint blockage therapies. The refinement of these therapeutic tools administered alone or in combination is a hot issue in oncology, and several international trials are underway