Purkinje Cell Outputs Selectively Inhibit a Subset of Unipolar Brush Cells in the Input Layer of the Cerebellar Cortex

Overview

Journal Elife

Specialty Biology

Date 2021 Aug 9

PMID 34369877

Citations 13

Authors

Chong Guo

Stephanie Rudolph

Morgan E Neuwirth

Wade G Regehr

Affiliations

Soon will be listed here.

Abstract

Circuitry of the cerebellar cortex is regionally and functionally specialized. Unipolar brush cells (UBCs), and Purkinje cell (PC) synapses made by axon collaterals in the granular layer, are both enriched in areas that control balance and eye movement. Here, we find a link between these specializations in mice: PCs preferentially inhibit metabotropic glutamate receptor type 1 (mGluR1)-expressing UBCs that respond to mossy fiber (MF) inputs with long lasting increases in firing, but PCs do not inhibit mGluR1-lacking UBCs. PCs inhibit about 29% of mGluR1-expressing UBCs by activating GABA receptors (GABARs) and inhibit almost all mGluR1-expressing UBCs by activating GABA receptors (GABARs). PC to UBC synapses allow PC output to regulate the input layer of the cerebellar cortex in diverse ways. Based on optogenetic studies and a small number of paired recordings, GABAR-mediated feedback is fast and unreliable. GABAR-mediated inhibition is slower and is sufficiently large to strongly influence the input-output transformations of mGluR1-expressing UBCs.

Citing Articles

Characterization of direct Purkinje cell outputs to the brainstem.

Chen C, Yao Z, Wu S, Regehr W Elife. 2025; 13.

PMID: 40013677 PMC: 11867612. DOI: 10.7554/eLife.101825.

Realistic mossy fiber input patterns to unipolar brush cells evoke a continuum of temporal responses comprised of components mediated by different glutamate receptors.

Huson V, Regehr W Elife. 2025; 13.

PMID: 39819796 PMC: 11741519. DOI: 10.7554/eLife.102618.

Characterization of direct Purkinje cell outputs to the brainstem.

Chen C, Yao Z, Wu S, Regehr W bioRxiv. 2024; .

PMID: 39605653 PMC: 11601412. DOI: 10.1101/2024.08.16.608221.

Increased understanding of complex neuronal circuits in the cerebellar cortex.

Jun S, Park H, Kim M, Kang S, Kim T, Kim D Front Cell Neurosci. 2024; 18:1487362.

PMID: 39497921 PMC: 11532081. DOI: 10.3389/fncel.2024.1487362.

Realistic mossy fiber input patterns to unipolar brush cells evoke a continuum of temporal responses comprised of components mediated by different glutamate receptors.

Huson V, Regehr W bioRxiv. 2024; .

PMID: 39345419 PMC: 11429827. DOI: 10.1101/2024.09.17.613480.

References

Siuda K, Chrobak A, Starowicz-Filip A, Tereszko A, Dudek D . [Emotional disorders in patients with cerebellar damage--case studies]. Psychiatr Pol. 2014; 48(2):289-97. View

Kozareva V, Martin C, Osorno T, Rudolph S, Guo C, Vanderburg C . A transcriptomic atlas of mouse cerebellar cortex comprehensively defines cell types. Nature. 2021; 598(7879):214-219. PMC: 8494635. DOI: 10.1038/s41586-021-03220-z. View

Sotelo C . Viewing the cerebellum through the eyes of Ramón Y Cajal. Cerebellum. 2008; 7(4):517-22. DOI: 10.1007/s12311-008-0078-0. View

Kaupmann K, Malitschek B, Schuler V, Heid J, Froestl W, Beck P . GABA(B)-receptor subtypes assemble into functional heteromeric complexes. Nature. 1999; 396(6712):683-7. DOI: 10.1038/25360. View

Nunzi M, Shigemoto R, Mugnaini E . Differential expression of calretinin and metabotropic glutamate receptor mGluR1alpha defines subsets of unipolar brush cells in mouse cerebellum. J Comp Neurol. 2002; 451(2):189-99. DOI: 10.1002/cne.10344. View

Tanaka I, Ezure K . Overall distribution of GLYT2 mRNA-containing versus GAD67 mRNA-containing neurons and colocalization of both mRNAs in midbrain, pons, and cerebellum in rats. Neurosci Res. 2004; 49(2):165-78. DOI: 10.1016/j.neures.2004.02.007. View

Witter L, Rudolph S, Pressler R, Lahlaf S, Regehr W . Purkinje Cell Collaterals Enable Output Signals from the Cerebellar Cortex to Feed Back to Purkinje Cells and Interneurons. Neuron. 2016; 91(2):312-9. PMC: 4969194. DOI: 10.1016/j.neuron.2016.05.037. View

Villanueva R . The cerebellum and neuropsychiatric disorders. Psychiatry Res. 2012; 198(3):527-32. DOI: 10.1016/j.psychres.2012.02.023. View

Gassmann M, Bettler B . Regulation of neuronal GABA(B) receptor functions by subunit composition. Nat Rev Neurosci. 2012; 13(6):380-94. DOI: 10.1038/nrn3249. View

10.

Dugue G, Dumoulin A, Triller A, Dieudonne S . Target-dependent use of co-released inhibitory transmitters at central synapses. J Neurosci. 2005; 25(28):6490-8. PMC: 6725433. DOI: 10.1523/JNEUROSCI.1500-05.2005. View

11.

Galvez T, Urwyler S, Prezeau L, Mosbacher J, Joly C, Malitschek B . Ca(2+) requirement for high-affinity gamma-aminobutyric acid (GABA) binding at GABA(B) receptors: involvement of serine 269 of the GABA(B)R1 subunit. Mol Pharmacol. 2000; 57(3):419-26. DOI: 10.1124/mol.57.3.419. View

12.

Cerminara N, Lang E, Sillitoe R, Apps R . Redefining the cerebellar cortex as an assembly of non-uniform Purkinje cell microcircuits. Nat Rev Neurosci. 2015; 16(2):79-93. PMC: 4476393. DOI: 10.1038/nrn3886. View

13.

Suvrathan A, Payne H, Raymond J . Timing Rules for Synaptic Plasticity Matched to Behavioral Function. Neuron. 2016; 92(5):959-967. PMC: 5165237. DOI: 10.1016/j.neuron.2016.10.022. View

14.

Guo C, Rudolph S, Neuwirth M, Regehr W . Purkinje cell outputs selectively inhibit a subset of unipolar brush cells in the input layer of the cerebellar cortex. Elife. 2021; 10. PMC: 8352585. DOI: 10.7554/eLife.68802. View

15.

Murdoch B . The cerebellum and language: historical perspective and review. Cortex. 2009; 46(7):858-68. DOI: 10.1016/j.cortex.2009.07.018. View

16.

Crook J, Hendrickson A, Erickson A, Possin D, ROBINSON F . Purkinje cell axon collaterals terminate on Cat-301+ neurons in Macaca monkey cerebellum. Neuroscience. 2007; 149(4):834-44. PMC: 2267770. DOI: 10.1016/j.neuroscience.2007.08.030. View

17.

Delvendahl I, Hallermann S . The Cerebellar Mossy Fiber Synapse as a Model for High-Frequency Transmission in the Mammalian CNS. Trends Neurosci. 2016; 39(11):722-737. DOI: 10.1016/j.tins.2016.09.006. View

18.

Knoflach F, Kemp J . Metabotropic glutamate group II receptors activate a G protein-coupled inwardly rectifying K+ current in neurones of the rat cerebellum. J Physiol. 1998; 509 ( Pt 2):347-54. PMC: 2230982. DOI: 10.1111/j.1469-7793.1998.347bn.x. View

19.

Locatelli F, Botta L, Prestori F, Masetto S, DAngelo E . Late-onset bursts evoked by mossy fibre bundle stimulation in unipolar brush cells: evidence for the involvement of H- and TRP-currents. J Physiol. 2012; 591(4):899-918. PMC: 3591705. DOI: 10.1113/jphysiol.2012.242180. View

20.

Hirono M, Saitow F, Kudo M, Suzuki H, Yanagawa Y, Yamada M . Cerebellar globular cells receive monoaminergic excitation and monosynaptic inhibition from Purkinje cells. PLoS One. 2012; 7(1):e29663. PMC: 3250469. DOI: 10.1371/journal.pone.0029663. View