Acetylcholine Modulates Cerebellar Granule Cell Spiking by Regulating the Balance of Synaptic Excitation and Inhibition

Abstract

Sensorimotor integration in the cerebellum is essential for refining motor output, and the first stage of this processing occurs in the granule cell layer. Recent evidence suggests that granule cell layer synaptic integration can be contextually modified, although the circuit mechanisms that could mediate such modulation remain largely unknown. Here we investigate the role of ACh in regulating granule cell layer synaptic integration in male rats and mice of both sexes. We find that Golgi cells, interneurons that provide the sole source of inhibition to the granule cell layer, express both nicotinic and muscarinic cholinergic receptors. While acute ACh application can modestly depolarize some Golgi cells, the net effect of longer, optogenetically induced ACh release is to strongly hyperpolarize Golgi cells. Golgi cell hyperpolarization by ACh leads to a significant reduction in both tonic and evoked granule cell synaptic inhibition. ACh also reduces glutamate release from mossy fibers by acting on presynaptic muscarinic receptors. Surprisingly, despite these consistent effects on Golgi cells and mossy fibers, ACh can either increase or decrease the spike probability of granule cells as measured by noninvasive cell-attached recordings. By constructing an integrate-and-fire model of granule cell layer population activity, we find that the direction of spike rate modulation can be accounted for predominately by the initial balance of excitation and inhibition onto individual granule cells. Together, these experiments demonstrate that ACh can modulate population-level granule cell responses by altering the ratios of excitation and inhibition at the first stage of cerebellar processing.

Projection-dependent heterogeneity of cerebellar granule cell calcium responses

“…These results suggest that the activity balance between D-GCs and M-GCs could be altered by the situations affecting the overall excitation-inhibition (E-I) balance in the GCL. A recent study reported that acetylcholine regulates the balance of synaptic excitation and inhibition in the GCL and consequently GC excitability [ 48 ]. Anatomical studies showed the presence of cholinergic projections into the cerebellum by the observation of choline acetyltransferase-positive MF-like terminals or thin beaded fibers originating from diverse sources [ 49 , 50 ].…”

Local synaptic inhibition mediates cerebellar granule cell pattern separation necessary for learned sensorimotor associations

“…Such measurements have not, however, revealed that consistency of mossy fiber input is translated into consistency of spike timing, which may vary considerably due to intrinsic membrane properties and other inputs. For example, while our experiments are designed to address fast synaptic inhibition provided by GABA A receptors, they do not address the contributions of GABA B receptors 54 , neuromodulators 38, 55 , or cell-intrinsic conductances, such as voltage-activated potassium currents, that can alter the relationship between synaptic input and spiking 39 . We also note that the reliability of inputs may be modality specific 56 , as different mossy fibers can have different strengths and short-term plasticity, and likely have different temporal consistency depending on source.…”

“…Because behavior and learning can be context-specific, we suggest that factors regulating granule cell inhibition may provide a powerful basis for enhancing patterns that should be learned or preventing learning in other contexts. In particular, Golgi cells can be bi-directionally modulated by acetylcholine and serotonin 38, 55 . Thus, our measurements suggest that these neuromodulators are likely candidates to enable context specific cerebellar behavior and learning.…”

“…While previous measurements have shown that the timing of mossy fiber input can be highly reproduceable across trials 53 , this may not translate into a consistency of granule cell spike timing. For example, GABA B receptors 54 , neuromodulators 40, 55 , and cell-intrinsic conductances such as voltage-activated potassium currents can all significantly alter the relationship between synaptic input and granule cell spiking 41 . The reliability of inputs may also be modality specific 56 , as different mossy fibers can have different strengths and short-term plasticity, and likely have different temporal consistency depending on source.…”

Regulating synchronous oscillations of cerebellar granule cells by different types of inhibition

“…The capacity of the brain to accommodate information precisely within a limited time window is important for reliable execution of complex sensory and motor behaviors [1,2]. When the cerebellar cortex is injured, the movement loses precision and becomes uncoordinated and incorrectly timed, occurring in both humans [3][4][5] and animals [6,7].…”