title: Degeneracy in the regulation of short-term plasticity and synaptic filtering by presynaptic mechanisms.
abstract: We develop a new biophysically rooted, physiologically constrained conductance-based synaptic model to mechanistically account for short-term facilitation and depression, respectively through residual calcium and transmitter depletion kinetics. We address the specific question of how presynaptic components (including voltage-gated ion channels, pumps, buffers and release-handling mechanisms) and interactions among them define synaptic filtering and short-term plasticity profiles. Employing global sensitivity analyses (GSAs), we show that near-identical synaptic filters and short-term plasticity profiles could emerge from disparate presynaptic parametric combinations with weak pairwise correlations. Using virtual knockout models, a technique to address the question of channel-specific contributions within the GSA framework, we unveil the differential and variable impact of each ion channel on synaptic physiology. Our conclusions strengthen the argument that parametric and interactional complexity in biological systems should not be viewed from the limited curse-of-dimensionality standpoint, but from the evolutionarily advantageous perspective of providing functional robustness through degeneracy.
  
  
  
  Information processing in neurons is known to emerge as a gestalt of pre- and post-synaptic filtering. However, the impact of presynaptic mechanisms on synaptic filters has not been quantitatively assessed. Here, we developed a biophysically rooted, conductance-based model synapse that was endowed with six different voltage-gated ion channels, calcium pumps, calcium buffer and neurotransmitter-replenishment mechanisms in the presynaptic terminal. We tuned our model to match the short-term plasticity profile and band-pass structure of Schaffer collateral synapses, and performed sensitivity analyses to demonstrate that presynaptic voltage-gated ion channels regulated synaptic filters through changes in excitability and associated calcium influx. These sensitivity analyses also revealed that calcium- and release-control mechanisms were effective regulators of synaptic filters, but accomplished this without changes in terminal excitability or calcium influx. Next, to perform global sensitivity analysis, we generated 7000 randomized models spanning 15 presynaptic parameters, and computed eight different physiological measurements in each of these models. We validated these models by applying experimentally obtained bounds on their measurements, and found 104 (∼1.5%) models to match the validation criteria for all eight measurements. Analysing these valid models, we demonstrate that analogous synaptic filters emerge from disparate combinations of presynaptic parameters exhibiting weak pairwise correlations. Finally, using virtual knockout models, we establish the variable and differential impact of different presynaptic channels on synaptic filters, underlining the critical importance of interactions among different presynaptic components in defining synaptic physiology. Our results have significant implications for protein-localization strategies required for physiological robustness and for degeneracy in long-term synaptic plasticity profiles.
authors.affiliation: Cellular Neurophysiology Laboratory, Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560012, India.
authors.forename: Chinmayee L
authors.initials: CL
authors.lastname: Mukunda
authors.affiliation: Cellular Neurophysiology Laboratory, Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560012, India.
authors.forename: Rishikesh
authors.identifier: 0000-0002-1362-4635
authors.initials: R
authors.lastname: Narayanan
mesh_terms: D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D008959:Models, Neurological; D009473:Neuronal Plasticity / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
keywords: computational model; degeneracy; global sensitivity analysis; paired-pulse ratio; presynaptic ion channels; synaptic physiology