RAGE signaling is required for AMPA receptor dysfunction in the hippocampus of hyperglycemic mice.

Diabetes in humans has been associated for a long time with cognitive dysfunction. In rodent animal models, cognitive dysfunction can manifest as impaired hippocampal synaptic plasticity. Particular attention has been concentrated on the receptor for advanced glycation end products (RAGE), which is implicated in multiple diabetic complications involving the development of vascular and peripheral nerve abnormalities. In this study, we hypothesize that RAGE signaling alters glutamate receptor function and expression, impairing synaptic transmission in the hippocampus. Using preparations of hippocampal slices from male mice, we show a RAGE-dependent decrease in long-term potentiation (LTP) and an increase in paired-pulse facilitation (PPF) following streptozotocin (STZ)-induced diabetes. Consistently, in hippocampal cultures from male and female neonatal mice, high glucose caused a RAGE-dependent reduction of AMPA- but not NMDA-evoked currents, and an increase in cytosolic reactive oxygen species (ROS). Consistently, when cultures were co-treated with high glucose and the RAGE antagonist FPS-ZM1, AMPA-evoked currents were unchanged. Hippocampi from STZ-induced hyperglycemic wild type (WT) mice showed increased RAGE expression concomitant with a decrease of both expression and phosphorylation (Ser 831 and 845) of the AMPA GluA1 subunit. We found these changes correlated to activation of the MAPK pathway, consistent with decreased pJNK/JNK ratio and the JNK kinase, pMEK7. As no changes in expression or phosphorylation of regulatory proteins were observed in hippocampi from STZ-induced hyperglycemic RAGE-KO mice, we report a RAGE-dependent impairment in the hippocampi of hyperglycemic WT mice, with reduced AMPA receptor expression/function and LTP deficits.

A Connected Community Approach: Citizens and Formal Institutions Working Together to Build Community-Centred Resilience.

Urban resilience research is recognizing the need to complement a mainstream preoccupation with "hard" infrastructure (electrical grid, storm sewers, etc.) with attention to the "soft" (social) infrastructure issues that include the increased visibility of and role for civil society, moving from (top-down, paternalistic) government to (participatory) governance. Analyses of past shock events invariably point to the need for more concerted efforts in building effective governance and networked relations between civil society groupings and formal institutions before, during, and after crisis. However, the literature contains little advice on how to go about this. In this paper, we advance a Connected Community Approach (CCA) to building community resilience with a specific focus on the relationship between community and formal institutions. In the literature review that informs this work, we assess the current, limited models for connecting communities to formal institutions, as well as the emerging role of community-based organizations in this work, and we offer our own assessment of some of the key tensions, lacunae, and trends in the community resilience field. Principally, we explore the potential of the CCA model, as spearheaded by the East Scarborough Storefront and the Centre for Connected Communities in Toronto, Canada, as a promising approach for building the relational space between civil society and the state that is so often called for in the literature. The paper concludes with future directions for research and practice.