Excitation and Inhibition Delays within a Feedforward Inhibitory Pathway Modulate Cerebellar Purkinje Cell Output in Mice

Abstract

The cerebellar cortex computes sensorimotor information from many brain areas through a feedforward inhibitory (FFI) microcircuit between the input stage, the granule cell layer, and the output stage, the Purkinje cells (PC). While in other brain areas FFI underlies a precise excitation vs. inhibition temporal correlation, recent findings in the cerebellum highlighted more complex behaviors at the granule cell (GC) – molecular layer interneuron (MLI) – PC pathway. To dissect the temporal organization of this cerebellar FFI pathway, we combined exvivo patch clamp recordings of PCs in male mice with a viral-based strategy to express Channelrhodopsin2 in a subset of mossy fibers (MFs), the major excitatory inputs to GCs. We show that while light-mediated MF activation elicited pairs of excitatory and inhibitory postsynaptic currents in PCs, excitation (E) from GCs and inhibition (I) from MLIs reached PCs with a wide range of different temporal delays. However, when GCs were directly stimulated, a low variability in E/I delays was observed. Our results demonstrate that in many recordings MF stimulation recruited different groups of GCs that trigger E and/or I, and expanded PCs temporal synaptic integration. Finally, using a computational model of the FFI pathway, we showed that this temporal expansion could strongly influence how PCs integrate GC inputs. Our findings show that specific E/I delays may help PCs encoding specific MF inputs.Significance statementSensorimotor information is conveyed to the cerebellar cortex by mossy fibers. Mossy fiber inputs activate granule cells that excite molecular interneurons and Purkinje cells, the sole output of the cerebellar cortex, leading to a sequence of synaptic excitation and inhibition in Purkinje cells, thus defining a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we demonstrated that different groups of granule cells can elicit synaptic excitation and inhibition with various latencies onto Purkinje cells. This temporal variability control how granule cells influence Purkinje cell discharge and may support temporal coding in the cerebellar cortex.

Feedback and Feedforward Regulation of Interneuronal Communication

“…The analysis of the incoherent feedforward circuit was restricted to the interneuron frequency being equal to the presynaptic input frequency, and future work will relax this assumption. Another interesting direction of future work is to use these analytical models of feedforward circuits (both coherent and incoherent) to study several reported invivo examples of such circuits and understand their function in different neurological contexts [51]- [53].…”

Purkinje cell models: past, present and future

“…The Fiala et al ( 1996 ) and Antunes and De Schutter ( 2012 ) synaptic models were used as basis for other synaptic models: the Steuber et al ( 2006 ) and Hepburn et al ( 2017 ) (in turn used for the Zamora Chimal and De Schutter, 2018 model), respectively. Finally, the Binda et al ( 2023 ) network model was based on the Grangeray-Vilmint et al ( 2018 ) model of the same type. Figure generated with BioRender.…”

“…In 2023, a network model based on the 2018 Grangeray-Vilmint model was used to investigate a temporal organization of the feedforward inhibitory microcircuit between GrCs, MLIs and PCs (Binda et al, 2023 ). Using ex vivo patch-clamp recordings of PCs and the Grangeray-Vilmint model, it was shown that the encoding of specific MF inputs by PCs can be aided by specific excitatory and inhibitory delays.…”