Zandt, B.-J. | bioRxiv Science

bioRxiv2019

GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons

The binding of GABA to extra-synaptic GABAA receptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present at low levels throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes through variation in chloride gradient. Here, we introduce a distinct mechanism through which extracellular GABA can differentially modulate the excitability of neuron subtypes through variation in neuronal electrophysiological properties. Using biophysically-detailed computational models, we found that tonic inhibition enhanced the responsiveness (or gain) of models with electrophysiological features typically observed in somatostatin (Sst) interneurons and reduced gain in models with features typical for parvalbumin (Pv) interneurons. These predictions were experimentally verified using patch-clamp recordings. Further analysis revealed that differential gain modulation is also dependent upon the extent of outward rectification of the GABAA receptor-mediated tonic current. Our detailed neuron models demonstrate two subcellular consequences of tonic inhibition. First, tonic inhibition enhances somatic action potential repolarisation by increasing current flow into the dendritic compartment. This enhanced repolarisation then reduces voltage-dependent potassium currents at the soma during the afterhyperpolarisation. Finally, we show that reductions of potassium current selectively increase gain within neurons exhibiting action potential dynamics typical for Sst interneurons. Potassium currents in Pv-type interneurons are not sensitive to this mechanism as they deactivate rapidly and are unavailable for further modulation. These findings introduce a neuromodulatory paradigm in which GABA can induce a state of differential interneuron excitability through differences in intrinsic electrophysiological properties.

neuroscience↗

bioRxiv2019

Experimentally-constrained biophysical models of tonic and burst firing modes in thalamocortical neurons

Somatosensory thalamocortical (TC) neurons from the ventrobasal (VB) thalamus are central components in the flow of sensory information between the periphery and the cerebral cortex, and participate in the dynamic regulation of thalamocortical states including wakefulness and sleep. This property is reflected at the cellular level by the ability to generate action potentials in two distinct firing modes, called tonic firing and low-threshold bursting. Although the general properties of TC neurons are known, we still lack a detailed characterization of their morphological and electrical properties in the VB thalamus. The aim of this study was to build biophysically-detailed models of VB TC neurons explicitly constrained with experimental data from rats. We recorded the electrical activity of VB neurons (N = 49) and reconstructed morphologies in 3D (N = 50) by applying standardized protocols. After identifying distinct electrical types, we used a multi-objective optimization to fit single neuron electrical models (e-models), which yielded multiple solutions consistent with the experimental data. The models were tested for generalization using electrical stimuli and neuron morphologies not used during fitting. A local sensitivity analysis revealed that the e-models are robust to small parameter changes and that all the parameters were constrained by one or more features. The e-models, when tested in combination with different morphologies, showed that the electrical behavior is substantially preserved when changing dendritic structure and that the e-models were not overfit to a specific morphology. The models and their analysis show that automatic parameter search can be applied to capture complex firing behavior, such as co-existence of tonic firing and low-threshold bursting over a wide range of parameter sets and in combination with different neuron morphologies.\n\nAuthor summaryThalamocortical neurons are one of the main components of the thalamocortical system, which are implicated in key functions including sensory transmission and the transition between brain states. These functions are reflected at the cellular level by the ability to generate action potentials in two distinct modes, called burst and tonic firing. Biophysically-detailed computational modeling of these cells can provide a tool to understand the role of these neurons within thalamocortical circuitry. We started by collecting single cell experimental data by applying standardized experimental procedures in brain slices of the rat. Prior work has demonstrated that biological constraints can be integrated using multi-objective optimization to build biologically realistic models of neuron. Here, we employ similar techniques as those previously employed, but extend them to capture the multiple firing modes of thalamic neurons. We compared the model results with additional experimental data test their generalization and quantitatively reject those that deviated significantly from the experimental variability. These models can be readily integrated in a data-driven pipeline to reconstruct and simulate circuit activity in the thalamocortical system.

neuroscience↗