5
Identification of an inhibitory circuit that regulates cerebellar Golgi cell activity.
Neuron. 2012 Jan 12; 73(1):149-58
All selected articles haveThis article has been added to your saved articles
You can follow/unfollow articles via MyF1000 or via the article or browse pages.
26 Jan 2012
New Finding, Refutation
DOI: 10.3410/f.13489067.14866195
This is an elegant study in which Hull and Regehr have presented findings that revise the generally accepted view of cerebellar circuitry, in particularly its inhibitory wiring diagram.
It was generally accepted that all major pathways of synaptic inhibition in the cerebellar cortex have been identified....Continue reading
It was generally accepted that all major pathways of synaptic inhibition in the cerebellar cortex have been identified....Continue reading
This is an elegant study in which Hull and Regehr have presented findings that revise the generally accepted view of cerebellar circuitry, in particularly its inhibitory wiring diagram.
It was generally accepted that all major pathways of synaptic inhibition in the cerebellar cortex have been identified. An important element of cerebellar network is the Golgi cell. Mossy fibers ([MFs] carrying information from different regions of the central nervous system [CNS]) provide excitatory drive to both Golgi cells and granule cells. In turn, Golgi cells inhibit granule cells and can also inhibit release from MFs. Thus, Golgi cells can gate activation of the cerebellar cortex by regulating the excitability of both granule cells and MFs. On the basis of indirect evidence {1,2}, it was suggested that molecular layer interneurons (MLIs) inhibit both Golgi cells and Purkinje cells (PCs) and may also be electrically coupled to Golgi cells via gap junctions {3}.
By using intact circuitry of cerebellar brain slices, paired recordings and optogenetic and pharmacological approaches, Hull and Regehr have presented multiple lines of evidence showing that, first, Golgi cells receive synaptic inhibition from other Golgi cells and, second, that there are neither chemical nor electrical synapses between MLIs and Golgi cells. Thus, Golgi cells and Purkinje cells receive unique sources of inhibition and can differently process shared granule cell inputs. The authors suggested that a reexamination of models of granule cell layer inhibition in response to the MF inputs {4-6} could shed new light on how inhibition contributes to information processing at the input stage of the cerebellar cortex.
It was generally accepted that all major pathways of synaptic inhibition in the cerebellar cortex have been identified. An important element of cerebellar network is the Golgi cell. Mossy fibers ([MFs] carrying information from different regions of the central nervous system [CNS]) provide excitatory drive to both Golgi cells and granule cells. In turn, Golgi cells inhibit granule cells and can also inhibit release from MFs. Thus, Golgi cells can gate activation of the cerebellar cortex by regulating the excitability of both granule cells and MFs. On the basis of indirect evidence {1,2}, it was suggested that molecular layer interneurons (MLIs) inhibit both Golgi cells and Purkinje cells (PCs) and may also be electrically coupled to Golgi cells via gap junctions {3}.
By using intact circuitry of cerebellar brain slices, paired recordings and optogenetic and pharmacological approaches, Hull and Regehr have presented multiple lines of evidence showing that, first, Golgi cells receive synaptic inhibition from other Golgi cells and, second, that there are neither chemical nor electrical synapses between MLIs and Golgi cells. Thus, Golgi cells and Purkinje cells receive unique sources of inhibition and can differently process shared granule cell inputs. The authors suggested that a reexamination of models of granule cell layer inhibition in response to the MF inputs {4-6} could shed new light on how inhibition contributes to information processing at the input stage of the cerebellar cortex.
References
1.
Palay and Chan-Palay, "Cerebellar Cortex." New York: Springer, 1974.
2.
IPSC kinetics at identified GABAergic and mixed GABAergic and glycinergic synapses onto cerebellar Golgi cells.
J Neurosci 2001 Aug 15; 16(21):6045-57
PMID: 11487628
3.
Specialized membrane junctions between neurons in the vertebrate cerebellar cortex.
J Cell Biol 1972 May; 2(53):271-89
PMID: 4537207
4.
Albus JS, Math Biosci 1971, 10:25-61.
5.
A theory of cerebellar cortex.
J Physiol (Lond) 1969 Jun; 2(202):437-70
PMID: 5784296
6.
Timing mechanisms in the cerebellum: testing predictions of a large-scale computer simulation.
J Neurosci 2000 Jul 15; 14(20):5516-25
PMID: 10884335
Disclosures
None declared
Add Comment
Deliagina T: F1000Prime Recommendation of [Hull C and Regehr WG, Neuron 2012, 73(1):149-58]. In F1000Prime, 26 Jan 2012; DOI: 10.3410/f.13489067.14866195. F1000Prime.com/13489067#eval14866195
13 Feb 2012
Controversial, New Finding
DOI: 10.3410/f.13489067.15095056
Using optogenetics and simultaneously recorded Golgi and Purkinje cells in the cerebellar cortex, the authors show that Golgi cell inhibition is mediated through GABAergic synapses from other Golgi cells. This finding challenges the traditional wisdom according to which Golgi cell inhibition is mediated...Continue reading
Using optogenetics and simultaneously recorded Golgi and Purkinje cells in the cerebellar cortex, the authors show that Golgi cell inhibition is mediated through GABAergic synapses from other Golgi cells. This finding challenges the traditional wisdom according to which Golgi cell inhibition is mediated through molecular layer interneurons.
The authors' recordings show that, following a mossy fiber input, molecular layer interneurons inhibit Purkinje cells 1-2ms after Golgi cells are themselves inhibited, rather than synchronously as previously hypothesized. This result can have important consequences in cerebellar circuitry models.
The authors' recordings show that, following a mossy fiber input, molecular layer interneurons inhibit Purkinje cells 1-2ms after Golgi cells are themselves inhibited, rather than synchronously as previously hypothesized. This result can have important consequences in cerebellar circuitry models.
Disclosures
None declared
Angelaki D: F1000Prime Recommendation of [Hull C and Regehr WG, Neuron 2012, 73(1):149-58]. In F1000Prime, 13 Feb 2012; DOI: 10.3410/f.13489067.15095056. F1000Prime.com/13489067#eval15095056
16 Feb 2012
New Finding
DOI: 10.3410/f.13489067.15270060
This elegant paper identifies a new element of the neural circuitry of the cerebellar cortex: GABAergic synaptic connections between Golgi cells, the main inhibitory cell type in the granule cell layer.
Golgi cells are the main GABAergic cell type in the granule cell layer, the input layer of the cerebellar...Continue reading
Golgi cells are the main GABAergic cell type in the granule cell layer, the input layer of the cerebellar...Continue reading
This elegant paper identifies a new element of the neural circuitry of the cerebellar cortex: GABAergic synaptic connections between Golgi cells, the main inhibitory cell type in the granule cell layer.
Golgi cells are the main GABAergic cell type in the granule cell layer, the input layer of the cerebellar cortex. They are connected to each other via electrical synapses but were not previously thought to be connected via chemical synapses – rather, it was thought that they receive feed-forward inhibition from molecular layer interneurons (MLIs).
The authors showed that optogenetic stimulation of the glutamatergic mossy fibers triggers excitation followed by inhibition of Golgi cells and that this inhibition arrives at the same time as inhibition onto granule cells, the main targets of Golgi cell axons. Paired recordings between Golgi cells showed that they are directly connected by GABAergic synapses, with an overall ~20% connection probability. Connections between MLIs and Golgi cells were never observed, a finding that was confirmed by optogenetic stimulation of the entire population of MLIs.
The functional significance of Golgi-Golgi synaptic inhibition is that while mossy fiber excitation is followed by inhibition within 2ms, granule cell excitation (via the parallel fiber connection with the Golgi cell dendrites in the molecular layer) overlaps with the inhibition. This suggests that an integration window exists for mossy fiber excitation but that granule cell excitation is unlikely to have precise temporal control over Golgi cell spiking.
The discovery of this new connection will, therefore, necessitate revision of theories about how temporal patterns of activity are generated within the input layer of the cerebellum.
Golgi cells are the main GABAergic cell type in the granule cell layer, the input layer of the cerebellar cortex. They are connected to each other via electrical synapses but were not previously thought to be connected via chemical synapses – rather, it was thought that they receive feed-forward inhibition from molecular layer interneurons (MLIs).
The authors showed that optogenetic stimulation of the glutamatergic mossy fibers triggers excitation followed by inhibition of Golgi cells and that this inhibition arrives at the same time as inhibition onto granule cells, the main targets of Golgi cell axons. Paired recordings between Golgi cells showed that they are directly connected by GABAergic synapses, with an overall ~20% connection probability. Connections between MLIs and Golgi cells were never observed, a finding that was confirmed by optogenetic stimulation of the entire population of MLIs.
The functional significance of Golgi-Golgi synaptic inhibition is that while mossy fiber excitation is followed by inhibition within 2ms, granule cell excitation (via the parallel fiber connection with the Golgi cell dendrites in the molecular layer) overlaps with the inhibition. This suggests that an integration window exists for mossy fiber excitation but that granule cell excitation is unlikely to have precise temporal control over Golgi cell spiking.
The discovery of this new connection will, therefore, necessitate revision of theories about how temporal patterns of activity are generated within the input layer of the cerebellum.
Disclosures
None declared
Hausser M and Van Welie I: F1000Prime Recommendation of [Hull C and Regehr WG, Neuron 2012, 73(1):149-58]. In F1000Prime, 16 Feb 2012; DOI: 10.3410/f.13489067.15270060. F1000Prime.com/13489067#eval15270060
F1000Prime Recommendations, Dissents and Comments for [Hull C and Regehr WG, Neuron 2012, 73(1):149-58]. In F1000Prime, 23 May 2013; F1000Prime.com/13489067
Only registered/signed-in users can make comments.
Sign in or Subscribe to create your user account and join the discussion.
Sign in or Subscribe to create your user account and join the discussion.
No comments yet.
Here we provide evidence that revises the inhibitory circuit diagram of the cerebellar cortex. It was previously thought that Golgi cells, interneurons that are the sole source of inhibition onto granule cells, were exclusively coupled via gap junctions. Moreover, Golgi cells were believed to receive GABAergic inhibition from molecular layer interneurons (MLIs). Here we challenge these views by optogenetically activating the cerebellar circuitry to determine the timing and pharmacology of inhibition onto Golgi cells and by performing paired recordings to directly assess synaptic connectivity. In contrast to current thought, we find that Golgi cells, not MLIs, make inhibitory GABAergic synapses onto other Golgi cells. As a result, MLI feedback does not regulate the Golgi cell network, and Golgi cells are inhibited approximately 2 ms before Purkinje cells, following a mossy fiber input. Hence, Golgi cells and Purkinje cells receive unique sources of inhibition and can differentially process shared granule cell inputs.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neuron.2011.10.030
PMID: 22243753
