Data-Driven Modelling of Inhibition and Ca2+ Cascades
- Jonas Ranft, Leandro G. Almeida, Pamela C. Rodriguez, Antoine Triller, Vincent Hakim. “An aggregation Aggregation-Removal Model for the Formation and Size Determination of Post-Synaptic Scaffold Domains.” PLoS computational biology 13.4 (2017): e1005516.
- Pamela C. Rodriguez, Leandro G. Almeida, Antoine Triller. “Continuous rearrangement of the postsynaptic gephyrin scaffolding domain: a super-resolution quantified and energetic approach.” bioRxiv (2017): 193698.
Synaptic function and plasticity depend both on neuronal activity and on a delicate balance between overall structural stability and the continuous rearrangement of its components. We approach its study by different means, quantifying morphological changes and energetic states of multi-molecular assemblies over time, particularly of inhibition-related proteins, or by modelling excitatory and inhibitory activity and its consequences on intracellular calcium and subsequent cascades.
Our main focus is to understand the effects on tuning inhibition and the consequences this has on the excitation-inhibition balance and dendritic integration.
What makes it exciting?
It is well known that inhibition is a key ingredient in dendritic integration, and it may depend sensitively on the spatial and temporal resolution. For example, inhibitory synapses present in spines, as those found in pyramidal neurons at the layer 2/3 of the cortex, are expected to have very different functionality to perisomatic ones. Both the spatial and temporal distribution of inhibitory synapses, as well as their morphologies and energetic states, raise exciting questions about their functionality and their effects on calcium signalling and plasticity.
What are the specific questions we want to address in the HBP?
We have already developed a method to study the clustering of scaffold protein gephyrin (Rodriguez et al. 2017), which forms postsynaptic clusters that play a key role in the stabilisation of receptors at inhibitory synapses (J. Ranft et al. 2017). We also want to address how inhibitory spatial and temporal resolution affects the neuronal activity and its consequences on plasticity. Particularly, we will be investigating how inhibition affects intracellular calcium signalling and the associated cascades.
What is our specific take?
We have been able to provide an energetic approach to the stability of inhibitory synapses (Rodriguez et al. 2017), relating it to its morphological shape. We are modelling the synaptic activity by using cable theory and Hodgkin-Huxley formalism. In this modelling approach, we will consider the calcium-dependent cascades due to synaptic activity and their effects on tuning synaptic strength.
In April 2017, we released a model on formation and size of post-synaptic scaffold domain, gephyrin and Glycine receptors. In September 2017, we released a study of the morphological and energetic states of post-synaptic clusters of scaffolding protein gephyrin and described a general approach. During the period of 2018/2019, we expect to publish our work on modelling excitation and inhibition with a fine spatial and temporal resolution. Our final aim is to have a model based on actual neuronal physiology, accounting for the computational capacities of dendritic arborisation. We also expect to finish a work on inhibition and its effects on calcium-dependent cascades and, ultimately, plasticity.
Who is Involved?
The following people are driving this effort:
- Antoine Triller, Ecole Normale Superieure de Paris
- Pablo Serna Martinez, Ecole Normale Superieure de Paris
Benefits to the Community
Model use: If you want to use some of the results of this work, you can find them in the respective links to the works listed above. In the close future, we expect to have use cases in the Brain Simulation Platform so you can launch them.