Dynamics of Fast and Slow Inhibition from Cerebellar Golgi Cells Allow Flexible Control of Synaptic Integration

Crowley, John; Fioravante, Diasynou; Regehr, Wade G.

doi:10.1016/j.neuron.2009.09.004

Cited by 71 publications

(85 citation statements)

References 68 publications

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“…Although fast stimulus-locked inhibition of granule cells has thus far been difficult to detect in vivo (37), our voltage-clamp recordings revealed sensory-evoked phasic and spillover inhibition in all granule cells, consistent with the view that Golgi cell axons strongly influence many hundreds of granule cells across the granular layer (15,47). Moreover, the prevalence of slow, spillovermediated IPSCs in granule cells suggests that indirect spillover activation of GABA A receptors is a major form of Golgi-cell signaling during sensory stimulation (21,37,48,49). Differences in the number of direct and indirect synaptic inputs in each glomerulus will determine the relative contribution of fast and slow IPSCs during sensory activation (21,30,49).…”

Section: Discussionsupporting

confidence: 84%

Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition

Duguid

Branco

Chadderton

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Classical feed-forward inhibition involves an excitation-inhibition sequence that enhances the temporal precision of neuronal responses by narrowing the window for synaptic integration. In the input layer of the cerebellum, feed-forward inhibition is thought to preserve the temporal fidelity of granule cell spikes during mossy fiber stimulation. Although this classical feed-forward inhibitory circuit has been demonstrated in vitro, the extent to which inhibition shapes granule cell sensory responses in vivo remains unresolved. Here we combined whole-cell patch-clamp recordings in vivo and dynamic clamp recordings in vitro to directly assess the impact of Golgi cell inhibition on sensory information transmission in the granule cell layer of the cerebellum. We show that the majority of granule cells in Crus II of the cerebrocerebellum receive sensoryevoked phasic and spillover inhibition prior to mossy fiber excitation. This preceding inhibition reduces granule cell excitability and sensory-evoked spike precision, but enhances sensory response reproducibility across the granule cell population. Our findings suggest that neighboring granule cells and Golgi cells can receive segregated and functionally distinct mossy fiber inputs, enabling Golgi cells to regulate the size and reproducibility of sensory responses.C lassical feed-forward inhibition (FFI) involves a sequence of excitation rapidly terminated by inhibition. This temporal sequence narrows the time window for synaptic integration and enforces precise spike timing (1-7). FFI is thought to be important for regulating the temporal fidelity of spike responses in many neural systems, including the motor system, where rapid and adaptable changes in muscle activity are essential for coordinated motor control (8-10). The cerebellum plays a central role in fine sculpting of movements, and damage to the cerebellum produces severe motor deficits, most notably enhanced temporal variability of voluntary movements (11,12). These findings suggest that cerebellar circuits have the ability to preserve precise timing information during behavior (5, 6, 13), and in vitro studies have shown that feed-forward inhibitory networks in the input layer of the cerebellum provide a mechanism for maintaining the temporal fidelity of information transmission (6,14,15).Synaptic inhibition in the granule cell layer is generated by Golgi cells, GABAergic interneurons that provide direct inhibitory input to granule cells (6,(15)(16)(17). The prevailing view is that, when mossy fibers are activated, granule cells receive both monosynaptic excitation and disynaptic FFI from Golgi cells, providing temporally precise inhibitory input that narrows the window for the temporal summation of discrete mossy fiber inputs (6,14,18). This classical excitation-inhibition sequence forms the basis of a variety of contemporary cerebellar models (7,9,18,19). However, the exact temporal relationship between sensory-evoked excitation and inhibition in granule cells has never been determined in vivo. Here, we c...

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Section: Discussionsupporting

confidence: 84%

Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition

Duguid

Branco

Chadderton

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Although these speculations are intriguing because of the use of serotonergic and antiglutamatergic drugs in PBA, the function of various cells and neurotransmitters within the cerebellar microcircuitry, or their specific role in PBA, has not been clearly defined, and researchers continue their efforts to elucidate potential mechanisms within this circuitry and their potential role in cerebro-cerebellar loops [50][51][52][53].…”

Section: Cerebellar Mechanismsmentioning

confidence: 99%

Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments

Miller¹,

Pratt

Schiffer³

2011

Expert Review of Neurotherapeutics

115

137

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“…The temporal aspects of GABAergic signaling (e.g., slow versus fast) have distinct computational consequences (Crowley et al, 2009;Pavlov et al, 2009). A previous study in cerebellar granule cells found that tonic GABA A R-mediated conductances affected both offset and gain of the I-O relationship with a noisy input (Mitchell and Silver, 2003).…”

Section: Effects Of Rectification Of the Tonic Conductance On Noise Amentioning

confidence: 99%

Outwardly Rectifying Tonically Active GABA_AReceptors in Pyramidal Cells Modulate Neuronal Offset, Not Gain

Pavlov

Savtchenko²,

Kullmann³

et al. 2009

J. Neurosci.

112

124

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Hippocampal pyramidal cell excitability is regulated both by fast synaptic inhibition and by tonically active high-affinity extrasynaptic GABA A receptors. The impact of tonic inhibition on neuronal gain and offset, and thus on information processing, is unclear. Offset is altered by shunting inhibition, and the gain of a neuronal response to an excitatory input can be modified by changing the level of "background" synaptic noise. Therefore, tonic activation of GABA A receptors would be expected to modulate offset and, in addition, to alter gain through a shunting effect on synaptic noise. Here we show that tonically active GABA A receptors in CA1 pyramidal cells show marked outward rectification, while the peaks of IPSCs exhibit a linear current-voltage relationship. As a result, tonic GABA A receptormediated currents have a minimal effect upon subthreshold membrane potential variation due to synaptic noise, but predominantly affect neurons at spiking threshold. Consistent with this, tonic GABA A receptor-mediated currents in pyramidal cells exclusively affect offset and not gain. Modulation of tonically active GABA A receptors by fluctuations in extracellular GABA concentrations or neuromodulators acting on high-affinity receptors potentially provides a powerful mechanism to alter neuronal offset independently of neuronal gain.

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Dynamics of Fast and Slow Inhibition from Cerebellar Golgi Cells Allow Flexible Control of Synaptic Integration

Cited by 71 publications

References 68 publications

Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition

Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition

Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments

Outwardly Rectifying Tonically Active GABA_AReceptors in Pyramidal Cells Modulate Neuronal Offset, Not Gain

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Dynamics of Fast and Slow Inhibition from Cerebellar Golgi Cells Allow Flexible Control of Synaptic Integration

Cited by 71 publications

References 68 publications

Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition

Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition

Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments

Outwardly Rectifying Tonically Active GABAAReceptors in Pyramidal Cells Modulate Neuronal Offset, Not Gain

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Product

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Outwardly Rectifying Tonically Active GABA_AReceptors in Pyramidal Cells Modulate Neuronal Offset, Not Gain