Serotonin regulates dynamics of cerebellar granule cell activity by modulating tonic inhibition

Abstract

26Understanding how afferent information is integrated by cortical structures requires identifying the 27 factors shaping excitation and inhibition within their input layers. The input layer of the cerebellar 28 cortex integrates diverse sensorimotor information to enable learned associations that refine the 29 dynamics of movement. Specifically, mossy fiber afferents relay sensorimotor input into the 30 cerebellum to excite granule cells, whose activity is regulated by inhibitory Golgi cells. To test 31 how this integration can be modulated, we have used an acute brain slice preparation from young 32 adult rats and found that encoding of mossy fiber input in the cerebellar granule cell layer can be 33 regulated by serotonin (5-HT) via a specific action on Golgi cells. We find that 5-HT depolarizes 34Golgi cells, likely by activating 5-HT2A receptors, but does not directly act on either granule cells 35 or mossy fibers. As a result of Golgi cell depolarization, 5-HT significantly increases tonic 36 inhibition onto both granule cells and Golgi cells. 5-HT-mediated Golgi cell depolarization is not 37 sufficient, however, to alter the probability or timing of mossy fiber-evoked feed-forward inhibition 38 onto granule cells. Together, increased granule cell tonic inhibition paired with normal feed-39 forward inhibition acts to reduce granule cell spike probability without altering spike timing. These 40 data hence provide a circuit mechanism by which 5-HT can reduce granule cell activity without 41 altering temporal representations of mossy fiber input. Such changes in network integration could 42 enable flexible, state-specific suppression of cerebellar sensorimotor input that should not be 43 learned, or enable reversal learning for unwanted associations. 44 45 New and Noteworthy 46 5-HT regulates synaptic integration at the input stage of cerebellar processing by increasing tonic 47 inhibition of granule cells. This circuit mechanism reduces the probability of granule cell spiking 48 without altering spike timing, thus suppressing cerebellar input without altering its temporal 49 representation in the granule cell layer. 50 51

Acetylcholine modulates cerebellar granule cell spiking by regulating the balance of synaptic excitation and inhibition

“…In contrast, blocking all ionotropic GABAergic inhibition (SR95531 5 μM) dramatically increased spike probabilities and rates uniformly across all recorded granule cells (muscarine: 1.2 ± 0.4 normalized, GABAzine: 6.8 ± 1.6; ANOVA F 1.076, 7.53 = 14.95, P=0.0049, n = 8, Figure 8C-G ). Consistent with the fast membrane time constant of granule cells (Fleming and Hull, 2019), however, neither muscarine nor SR95531 altered the timing of the first spikes in response to stimulation (mean ± S.D. stim 1: control = 3.5 ± 1.3 ms, musc = 4.3 ± 2.0 ms; stim 2: control = 2.3 ± 0.8 ms, musc = 2.5 ± 1.4 ms; stim 3: control = 2.5 ± 1.2 ms, musc = 2.8 ± 1.4 ms; n=5; Figure 8H ).…”

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

“…8G,H, insets). Consistent with the fast membrane time constant of granule cells (Fleming and Hull, 2019), however, neither muscarine nor SR95531 altered the timing of the first spikes in response to stimulation in the five cells that maintained firing in the presence of muscarine ( p Ͼ 0.05 for all conditions relative to control, except third stimulus in SR95531; Fig. 8J ).…”

“…), were used for extracellular stimulation of the mossy fiber tract. Cell-attached recordings were performed to avoid changes in granule cell excitability over time with whole-cell dialysis (Fleming and Hull, 2019). For these experiments, only cells with an initial spike probability in control conditions between ϳ20% and 60% were recorded to allow for increases or decreases in spike rate during pharmacological manipulations.…”

Calcium channel-dependent induction of long-term synaptic plasticity at excitatory Golgi cell synapses of cerebellum

“…While excitatory synapses are activated by mossy fibers as well as in granule cells through their ascending axons and parallel fibers (Cesana et al, 2013), inhibitory synapses are provided by neighboring Golgi cells (Hull and Regehr, 2012) and from Lugaro cells, while inputs from stellate and basket cells are still disputed (Dieudonne, 1998;Bureau et al, 2000;Misra et al, 2000). Moreover, neuromodulators could also bias Golgi cell membrane potential (Geurts et al, 2002;Schweighofer et al, 2004;Fleming and Hull, 2019). The activity of Golgi cells can also be influenced by the climbing fibers (Xu and Edgley, 2008) although the mechanisms is unclear and direct synaptic contacts have not been demonstrated (Galliano et al, 2013).…”