ABSTRACT
Experience-dependent plasticity is a key feature of brain synapses for which neuronal N-Methyl-D-Aspartate receptors (NMDARs) play a major role, from developmental circuit refinement to learning and memory. Astrocytes also express NMDARs, although their exact function has remained controversial. Here, we identify in mouse hippocampus, a circuit function for GluN2C NMDAR, a subtype highly expressed in astrocytes, in layer-specific tuning of synaptic strengths in CA1 pyramidal neurons. Interfering with astrocyte NMDAR or GluN2C NMDAR activity reduces the range of presynaptic strength distribution specifically in the stratum radiatum inputs without an appreciable change in the mean presynaptic strength. Mathematical modeling shows that narrowing of the width of presynaptic release probability distribution compromises the expression of long-term synaptic plasticity. Our findings suggest a novel feedback signaling system that uses astrocyte GluN2C NMDARs to adjust basal synaptic weight distribution of Schaffer collateral inputs, which in turn impacts computations performed by the CA1 pyramidal neuron.
Subject(s)
CA1 Region, Hippocampal/physiology , Neuronal Plasticity/physiology , Pyramidal Cells/physiology , Receptors, N-Methyl-D-Aspartate/genetics , Animals , Mice , Receptors, N-Methyl-D-Aspartate/metabolismABSTRACT
Several decades of cumulated research evidence have proven that aggregation of beta-amyloid 42 (Aß42) is the main cause of neuronal death in the brains of patients with Alzheimer's disease. Therefore, inhibition of Aß42 aggregation holds great promise for the prevention and treatment of Alzheimer's disease. To this end, we used a systematic in vitro evolution including a paired peptide library method. We identified two peptides with high binding affinity (with Kd in the nm range) for Aß42. Functionally, these peptides strongly inhibited the aggregation of Aß42 as shown by the thioflavin T assay and atomic force microscopy. Moreover, these peptides rescued PC12 cells from the cytotoxic effect of aggregated Aß42 in vitro. Our results suggest that these novel peptides may be potential therapeutic seeds for the treatment of Alzheimer's disease.
Subject(s)
Amyloid beta-Peptides/metabolism , Peptide Fragments/metabolism , Peptides/metabolism , Amino Acid Sequence , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/pharmacology , Animals , Cell Survival/drug effects , Fluorescein/chemistry , Kinetics , Microscopy, Atomic Force , Molecular Sequence Data , PC12 Cells , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , Peptide Library , Peptides/chemistry , Peptides/pharmacology , Protein Binding , Rats , Surface Plasmon ResonanceABSTRACT
Enzymes are regulated by their activation and inhibition. Enzyme activators can often be effective tools for scientific and medical purposes, although they are more difficult to obtain than inhibitors. Here, using the paired peptide method, we report on protease-cathepsin-E-activating peptides that are obtained at neutral pH. These selected peptides also underwent molecular evolution, after which their cathepsin E activation capability improved. Thus, the activators we obtained could enhance cathepsin-E-induced cancer cell apoptosis, which indicated their potential as cancer drug precursors.
