Regulation of output spike patterns by phasic inhibition in cerebellar granule cells

Thierry R. Nieus, Lisa Mapelli, Egidio D'Angelo

Research output: Contribution to journalArticle

Abstract

The complex interplay of multiple molecular mechanisms taking part to synaptic integration is hard to disentangle experimentally. Therefore, we developed a biologically realistic computational model based on the rich set of data characterizing the cerebellar glomerulus microcircuit. A specific issue was to determine the relative role of phasic and tonic inhibition in dynamically regulating granule cell firing, which has not been clarified yet. The model comprised the excitatory mossy fiber-granule cell and the inhibitory Golgi cell-granule cell synapses and accounted for vesicular release processes, neurotransmitter diffusion and activation of different receptor subtypes. Phasic inhibition was based on stochastic GABA release and spillover causing activation of two major classes of postsynaptic receptors, α1 and α6, while tonic inhibition was based on steady regulation of a Cl- leakage. The glomerular microcircuit model was validated against experimental responses to mossy fiber bursts while metabotropic receptors were blocked. Simulations showed that phasic inhibition controlled the number of spikes during burst transmission but predicted that it specifically controlled time-related parameters (firing initiation and conclusion and first spike precision) when the relative phase of excitation and inhibition was changed. In all conditions, the overall impact of α6 was larger than that of α1 subunit-containing receptors. However, α1 receptors controlled granule cell responses in a narrow ±10 ms band while α6 receptors showed broader ±50 ms tuning. Tonic inhibition biased these effects without changing their nature substantially. These simulations imply that phasic inhibitory mechanisms can dynamically regulate output spike patterns, as well as calcium influx and NMDA currents, at the mossy fiber-granule cell relay of cerebellum without the intervention of tonic inhibition.

Original languageEnglish
Article number246
JournalFrontiers in Cellular Neuroscience
Volume8
Issue numberAUG
DOIs
Publication statusPublished - Aug 25 2014

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N-Methylaspartate
Synapses
Cerebellum
gamma-Aminobutyric Acid
Neurotransmitter Agents
Calcium
Datasets

Keywords

  • Cerebellum
  • GABA-A receptors
  • Granule cell
  • Modeling
  • Spike timing
  • Synaptic inhibition

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Regulation of output spike patterns by phasic inhibition in cerebellar granule cells. / Nieus, Thierry R.; Mapelli, Lisa; D'Angelo, Egidio.

In: Frontiers in Cellular Neuroscience, Vol. 8, No. AUG, 246, 25.08.2014.

Research output: Contribution to journalArticle

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