Diverse Neuron Properties and Complex Network Dynamics in the Cerebellar Cortical Inhibitory Circuit

Abstract

Neuronal inhibition can be defined as a spatiotemporal restriction or suppression of local microcircuit activity. The importance of inhibition relies in its fundamental role in shaping signal processing in single neurons and neuronal circuits. In this context, the activity of inhibitory interneurons proved the key to endow networks with complex computational and dynamic properties. In the last 50 years, the prevailing view on the functional role of cerebellar cortical inhibitory circuits was that excitatory and inhibitory inputs sum spatially and temporally in order to determine the motor output through Purkinje cells (PCs). Consequently, cerebellar inhibition has traditionally been conceived in terms of restricting or blocking excitation. This assumption has been challenged, in particular in the cerebellar cortex where all neurons except granule cells (and unipolar brush cells in specific lobules) are inhibitory and fire spontaneously at high rates. Recently, a combination of electrophysiological recordings in vitro and in vivo, imaging, optogenetics and computational modeling, has revealed that inhibitory interneurons play a much more complex role in regulating cerebellar microcircuit functions: inhibition shapes neuronal response dynamics in the whole circuit and eventually regulate the PC output. This review elaborates current knowledge on cerebellar inhibitory interneurons [Golgi cells, Lugaro cells (LCs), basket cells (BCs) and stellate cells (SCs)], starting from their ontogenesis and moving up to their morphological, physiological and plastic properties, and integrates this knowledge with that on the more renown granule cells and PCs. We will focus on the circuit loops in which these interneurons are involved and on the way they generate feed-forward, feedback and lateral inhibition along with complex spatio-temporal response dynamics. In this perspective, inhibitory interneurons emerge as the real controllers of cerebellar functioning.

The Optogenetic Revolution in Cerebellar Investigations

“…Granule cells are excitatory neurons that make synaptic contacts (through the ascending axon or the parallel fibers) with the Golgi cells, molecular layer interneurons, and Purkinje cell (PC) dendrites (in the molecular layer, the external layer of the cerebellar cortex; in between, PCs soma originate the Purkinje cell layer). Interestingly, granule cells are the only excitatory neurons in the cerebellar cortex (except for unipolar brush cells in specific regions), giving rise to an inhibitory organization in feedback and feedforward loops that endow the cortical processing with peculiar features (for a detailed review of this topic see [10][11][12]). Another set of inputs comes from the climbing fibers, originating in the inferior olive.…”

Stellate cell computational modelling predicts signal filtering in the molecular layer circuit of cerebellum

“…Conversely, the axons branched immediately generating short and circumscribed collaterals (AIS length: 28.0±6.7 m, n = 4; axon length: 577.9 ± 225.0 m, n = 4; Supplementary Table 2 and Movie 1). The dendritic tree was flattened on the sagittal plane of the folium and the axon, after an initial part parallel to the dendrite, advanced along the transverse plane (Palay and Chan-Palay, 1974;Rieubland et al, 2014;Prestori et al, 2019). The 4 morphologies were transformed into morpho-electrical equivalents (Fig.…”

“…Inhibition provided by ML interneurons proved also able to regulate the bandwidth of PC responses in spots and beams (Cohen and Yarom, 2000;Mapelli et al, 2010). Although the importance of SCs, there is little knowledge on their mechanisms of action (for a recent review see (Prestori et al, 2019)).…”

Synergistic excitability plasticity in cerebellar functioning

“…Since that time, researchers have spent over five decades further elucidating the mechanism of cerebellar functioning. Following theoretical expectations, the discovery of plasticity of synaptic responsiveness is widely accepted as the basis of cerebellar learning and memory [7][8][9][10][11][12][13][14][15][16][17][18][19].…”

“…A recent review by Titley et al [42] has assisted in elucidating the functions of intrinsic excitability plasticity as the gain modulation at the cellular level. While the input-output computation of PCs is the sole outflow of the cerebellar cortex, it is necessary to further understand the orchestrated activity and synergy between the plasticity of excitatory and inhibitory synapses and the intrinsic excitability in the circuit [16,19]. However, it is difficult to detect the evidence of synergy in vivo and in vitro during learning paradigms.…”