SummaryTraditionally, NMDA receptors are located postsynaptically; yet, putatively presynaptic NMDA receptors (preNMDARs) have been reported. Although implicated in controlling synaptic plasticity, their function is not well understood and their expression patterns are debated. We demonstrate that, in layer 5 of developing mouse visual cortex, preNMDARs specifically control synaptic transmission at pyramidal cell inputs to other pyramidal cells and to Martinotti cells, while leaving those to basket cells unaffected. We also reveal a type of interneuron that mediates ascending inhibition. In agreement with synapse-specific expression, we find preNMDAR-mediated calcium signals in a subset of pyramidal cell terminals. A tuned network model predicts that preNMDARs specifically reroute information flow in local circuits during high-frequency firing, in particular by impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells, a finding that we experimentally verify. We conclude that postsynaptic cell type determines presynaptic terminal molecular identity and that preNMDARs govern information processing in neocortical columns.

Presynaptic NMDA receptors (preNMDARs) control synaptic release, but it is not well understood how. Rab3-interacting molecules (RIMs) provide scaffolding at presynaptic active zones and are involved in vesicle priming. Moreover, c-Jun N-terminal kinase (JNK) has been implicated in regulation of spontaneous release. We demonstrate that, at connected layer 5 pyramidal cell pairs of developing mouse visual cortex, Mg-sensitive preNMDAR signaling upregulates replenishment of the readily releasable vesicle pool during high-frequency firing. In conditional RIM1αβ deletion mice, preNMDAR upregulation of vesicle replenishment was abolished, yet preNMDAR control of spontaneous release was unaffected. Conversely, JNK2 blockade prevented Mg-insensitive preNMDAR signaling from regulating spontaneous release, but preNMDAR control of evoked release remained intact. We thus discovered that preNMDARs signal differentially to control evoked and spontaneous release by independent and non-overlapping mechanisms. Our findings suggest that preNMDARs may sometimes signal metabotropically and support the emerging principle that evoked and spontaneous release are distinct processes. VIDEO ABSTRACT.

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SummaryDiabetic subjects have been shownt oh avea ltered fibrin network structures.One proposedmechanism forthis is non-enzymaticglycation of fibrinogendue to highbloodglucose.We investigatedwhether glycaemic control would result in altered fibrin networkstructures duetodecreasedfibrinogen glycation. Tw enty uncontrolledtype 2diabetic subjects were treatedwith insulin in ordert oa chieve glycaemic control. Tw enty age-a nd bodymass index(BMI)-matched non-diabetic subjects were included as ar eference group.Purified fibrinogen, isolated from plasma sampleswas usedfor analysis.Therewas asignificant decrease in fibrinogen glycation (6.81 to 5.02mol glucose/mol fibrinogen) with acorresponding decrease in rate of lateralaggregation (5.86 to 4.62) and increasedpermeability(2.45 to 2.85 x 10 -8 cm 2 )a nd lysisr ate (3.08 to 3.27 µm/min) in the diabetic subjects afterglycaemic control.Thesevariablescorrelated with Keywords Diabetes,fibrin network,fibrinogen glycation,glycaemic control, hyperglycaemia markerso fg lycaemic control. Fibrin clots of non-diabetic subjects had as ignificantly higherr atio of inelastic to elastic deformation than thed iabetic subjects (0.10 vs.0.09).Although there was no difference in median fiber diameterbetween diabetic and non-diabetic subjects,there was asmallincrease in the proportion of thicker fibers in the diabetic samplesa fter glycaemic control.Results from SDS-PAGEindicated no detectable difference in factor XIIIa-crosslinking of fibrin clotsbetween uncontrolled and controlled diabetic samples. Diabetic subjects mayhavealtered fibrin networkf ormation kineticswhich contributes to decreasedp ores ize and lysisr ate of fibrinc lots. Achievement of glycaemiccontroland decreasedfibrinogen glycation levelimprovespermeabilityand lysisratesinapurified fibrinogen model.

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