Literature context: G2a Thermo Fisher Cat# A-21241; RRID:AB_2535810 Streptavidin-HRP conjugate Sigm
Neuroligin-neurexin (NL-NRX) complexes are fundamental synaptic organizers in the central nervous system. An accurate spatial and temporal control of NL-NRX signaling is crucial to balance excitatory and inhibitory neurotransmission, and perturbations are linked with neurodevelopmental and psychiatric disorders. MDGA proteins bind NLs and control their function and interaction with NRXs via unknown mechanisms. Here, we report crystal structures of MDGA1, the NL1-MDGA1 complex, and a spliced NL1 isoform. Two large, multi-domain MDGA molecules fold into rigid triangular structures, cradling a dimeric NL to prevent NRX binding. Structural analyses guided the discovery of a broad, splicing-modulated interaction network between MDGA and NL family members and helped rationalize the impact of autism-linked mutations. We demonstrate that expression levels largely determine whether MDGAs act selectively or suppress the synapse organizing function of multiple NLs. These results illustrate a potentially brain-wide regulatory mechanism for NL-NRX signaling modulation.
Literature context: Fisher Scientific Cat# A21241; RRID:AB_2535810 Goat anti-Rabbit IgG (H+L) Seco
Input-timing-dependent plasticity (ITDP) is a circuit-based synaptic learning rule by which paired activation of entorhinal cortical (EC) and Schaffer collateral (SC) inputs to hippocampal CA1 pyramidal neurons (PNs) produces a long-term enhancement of SC excitation. We now find that paired stimulation of EC and SC inputs also induces ITDP of SC excitation of CA2 PNs. However, whereas CA1 ITDP results from long-term depression of feedforward inhibition (iLTD) as a result of activation of CB1 endocannabinoid receptors on cholecystokinin-expressing interneurons, CA2 ITDP results from iLTD through activation of δ-opioid receptors on parvalbumin-expressing interneurons. Furthermore, whereas CA1 ITDP has been previously linked to enhanced specificity of contextual memory, we find that CA2 ITDP is associated with enhanced social memory. Thus, ITDP may provide a general synaptic learning rule for distinct forms of hippocampal-dependent memory mediated by distinct hippocampal regions.
Literature context: #A-21241; RRID:AB_2535810 Goat anti-
Age-related macular degeneration (AMD) affects the retinal pigment epithelium (RPE), a cell monolayer essential for photoreceptor survival, and is the leading cause of vision loss in the elderly. There are no disease-altering therapies for dry AMD, which is characterized by accumulation of subretinal drusen deposits and complement-driven inflammation. We report the derivation of human-induced pluripotent stem cells (hiPSCs) from patients with diagnosed AMD, including two donors with the rare ARMS2/HTRA1 homozygous genotype. The hiPSC-derived RPE cells produce several AMD/drusen-related proteins, and those from the AMD donors show significantly increased complement and inflammatory factors, which are most exaggerated in the ARMS2/HTRA1 lines. Using a panel of AMD biomarkers and candidate drug screening, combined with transcriptome analysis, we discover that nicotinamide (NAM) ameliorated disease-related phenotypes by inhibiting drusen proteins and inflammatory and complement factors while upregulating nucleosome, ribosome, and chromatin-modifying genes. Thus, targeting NAM-regulated pathways is a promising avenue for developing therapeutics to combat AMD.
We found that the secreted protein periostin (Postn) is highly induced after partial pancreatectomy in regenerating areas containing mesenchymal stroma and tubular complexes. Importantly, after partial pancreatectomy, Postn-deficient mice exhibit impaired mesenchymal formation and reduced regeneration specifically within the pancreatic β-cell compartment. Furthermore, Postn-deficient mice demonstrate an increased sensitivity to streptozotocin. Notably, injection of Postn directly into the pancreas stimulated proliferation of vimentin-expressing cells within 24 hours, and by 3 days, a mesenchymal stroma was present containing proliferating duct-like cells expressing the progenitor markers Ngn3 and Pdx1. Intraperitoneal injection of Postn resulted in increased numbers of islets and long-term glucoregulatory benefits with no adverse effects found in other tissues. Delivery of Postn throughout the pancreas via the common bile duct resulted in increased numbers of small insulin-expressing clusters and a significant improvement in glucose tolerance. Therefore, Postn is novel molecule capable of potentiating pancreatic β-cell regeneration.