Complement is involved in developmental synaptic pruning and pathological synapse loss in Alzheimer's disease. It is posited that C1 binding initiates complement activation on synapses; C3 fragments then tag them for microglial phagocytosis. However, the precise mechanisms of complement-mediated synaptic loss remain unclear, and the role of the lytic membrane attack complex (MAC) is unexplored. We here address several knowledge gaps: (i) is complement activated through to MAC at the synapse? (ii) does MAC contribute to synaptic loss? (iii) can MAC inhibition prevent synaptic loss? Novel methods were developed and optimised to quantify C1q, C3 fragments and MAC in total and regional brain homogenates and synaptoneurosomes from WT and AppNL-G-F Alzheimer's disease model mouse brains at 3, 6, 9 and 12 months of age. The impact on synapse loss of systemic treatment with a MAC blocking antibody and gene knockout of a MAC component was assessed in Alzheimer's disease model mice. A significant increase in C1q, C3 fragments and MAC was observed in AppNL-G-F mice compared to controls, increasing with age and severity. Administration of anti-C7 antibody to AppNL-G-F mice modulated synapse loss, reflected by the density of dendritic spines in the vicinity of plaques. Constitutive knockout of C6 significantly reduced synapse loss in 3xTg-AD mice. We demonstrate that complement dysregulation occurs in Alzheimer's disease mice involving the activation (C1q; C3b/iC3b) and terminal (MAC) pathways in brain areas associated with pathology. Inhibition or ablation of MAC formation reduced synapse loss in two Alzheimer's disease mouse models, demonstrating that MAC formation is a driver of synapse loss. We suggest that MAC directly damages synapses, analogous to neuromuscular junction destruction in myasthenia gravis.
Synapse 2 For Mac
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Despite calibration and even with the same inputs and weights, theoutputs of the different neurons are not identical. On the one hand,each output has a statistical noise due to the analog nature of theneuron, on the other hand, fixed-pattern deviations show up between theindividual neurons. Especially in the case of small inputs, a spatialcorrelation may also become apparent, resulting from different distancesto the synapse drivers.
--packages com.microsoft.azure:synapseml_2.12:0.10.1 specifies the dependency on synapseml_2.12 version 0.10.1;microsoft-spark-3-2_2.12-2.1.1.jar specifies Microsoft.Spark version 2.1.1 and Spark version 3.2
Projection neurons shape the activity of many neural networks. In particular, neuromodulatory substances, which are often released by projection neurons, alter the cellular and/or synaptic properties within a target network. However, neural networks in turn influence projection neuron input via synaptic feedback. This dissertation uses mathematical and biophysically-realistic modeling to investigate these issues in the gastric mill (chewing) motor network of the crab, Cancer borealis. The projection neuron MCN1 elicits a gastric mill rhythm in which the LG neuron and INTl burst in anti-phase due to their reciprocal inhibition. However, bath application of the neuromodulator PK elicits a similar gastric mill rhythm in the absence of MCN 1 participation; yet, the mechanism that underlies the PK-elicited rhythm is unknown. This dissertation develops a 2-dimensional model that is used to propose three potential mechanisms by which PK can elicit a similar gastric mill rhythm. The network dynamics of the MCN 1-elicited and PK-elicited rhythms are also compared using geometrical properties in the phase plane. Next, the two gastric mill rhythms are compared using a more biophysically-realistic model. Presynaptic inhibition of MCN 1 is necessary for coordinating network activity during the MCN 1-elicited rhythm. In contrast, the PK-elicited rhythm is shown to be coordinated by a synapse that is not functional during the MCN 1-elicited rhythm.
Next, the gastric mill rhythm that is elicited by two coactive projection neurons (MCNl and CPN2) is studied. A 2-dimensional model is used to compare the network dynamics of the MCN 1-elicited and MCN 1 /CPN2-elicited gastric mill rhythms via geometrical properties in the phase plane. While the MCN 1-elicited rhythm requires the presence of reciprocal inhibition between INTl and the LG neuron, the MCN I /CPN2-elicited rhythm persists in the absence of this reciprocal inhibition, due to an inhibitory feedback synapse from INTl to CPN2 that changes the locus of coordination in the gastric mill rhythm. Next, the effect of a second feedback synapse, from the AB neuron to MCN 1, is shown to change the motor pattern of the MCN 1- and MCN1/CPN2-elicited rhythms. Finally, a third MCNI/CPN2-elicited rhythm is studied where the AB to MCN 1 feedback synapse only affects the LG burst phase of the rhythm. 2ff7e9595c
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