| Details: |
Glutamatergic neurotransmission is of key importance for short-term and long-term plasticity in the hippocampus, which are underlying processes of memory and learning. Short-term plasticity is mainly regulated by the presynaptic neuron and long-term plasticity is to large parts regulated by the post-synaptic neuron. We have investigated two key biophysical mechanisms in glutamatergic hippocampal neurons with the help of whole-cell voltage-clamp in autaptic cultures and mathematical modelling.
In study 1 we looked into the role of intrinsic vesicle fusogenicity on short-term plasticity by formulating a deterministic vesicular release model based on ordinary differential equations. The model was able to simulate properties of resting neurons, by reproducing the spontaneous release rates and the size of the readily releasable pool. Furthermore, assuming that the heterogeneity in vesicular release probability arises due to differences in intrinsic vesicular fusogenicity, the model was able to explain depression by an imbalance between fusion and vesicular priming. It also predicted that facilitation could be due to an increase in intrinsic vesicular fusogenicity, which together with build-up of calcium gave rise to initial increase in vesicular release. Finally, we investigated the effect of three different modes of regulation of release probability on short-term plasticity. It was seen that differences in intrinsic vesicular fusogenicity gave rise to a more significant change in short-term plasticity than change in calcium sensitivity of release. All in all the results tell us that intrinsic vesicular fusogenicity has an important role in tuning short-term plasticity.
In study 2 we investigated the regulation of the postsynaptic allosteric AMPA receptor. To do this we developed a model based on the Monod Wyman Changeux framework which described the ligand concentration dependence of the conductance states by increasing affinity to conductance states. The model was able to explain thermodynamic behaviours of native and recombinant receptors when stimulated with full like glutamate and quisqualate as well as partial agonists like willardiines. It was also predicted that the receptor stabilizes its large conductance state within the time of spontaneous EPSC rise time, providing an underlying mechanism for the peak of the current.
|