Abstract
Neurons of the cerebellar nuclei generate the non-vestibular output of the cerebellum. Like other neurons, they integrate excitatory and inhibitory synaptic inputs and filter them through their intrinsic properties to produce patterns of action potential output. The synaptic and intrinsic features of cerebellar nuclear cells are unusual in several respects, however: these neurons receive an overwhelming amount of basal and driven inhibition from Purkinje neurons, but are also spontaneously active, producing action potentials even without excitation. Moreover, not only is spiking by nuclear cells sensitive to the amount of inhibition, but the strength of inhibition is also sensitive to the amount of spiking, through multiple forms of long-term plasticity. Here, we review the properties of synaptic excitation and inhibition, their short-term plasticity, and their influence on action potential firing of cerebellar nuclear neurons, as well as the interactions among excitation, inhibition, and spiking that produce long-term changes in synaptic strength. The data provide evidence that electrical and synaptic signaling in the cerebellar circuit is both plastic and resilient: the strength of IPSPs and EPSPs readily changes as the activity of cerebellar nuclear cells is modified. Notably, however, many of the identified forms of plasticity have an apparently homeostatic effect, responding to perturbations of input by restoring cerebellar output toward pre-perturbation values. Such forms of self-regulation appear consistent with the role of cerebellar output in coordinating movements. In contrast, other forms of plasticity in nuclear cells, including a long-term potentiation of excitatory postsynaptic currents (EPSCs) and excitation-driven increases in intrinsic excitability, are non-homeostatic, and instead appear suited to bring the circuit to a new set point. Interestingly, the combinations of inhibitory and excitatory stimuli that potentiate EPSCs resemble patterns of activity predicted to occur during eyelid conditioning, suggesting that this form long-term potentiation, perhaps amplified by intrinsic plasticity, may represent a cellular mechanism that is engaged during cerebellar learning.
Similar content being viewed by others
References
Chan-Palay V (1977) Cerebellar dentate nucleus. Organization, Cytology, and Transmitters. Springer, New York
Teune TM, van der Burg J, Ruigrok TJ (1995) Cerebellar projections to the red nucleus and inferior olive originate from separate populations of neurons in the rat: a non-fluorescent double labeling study. Brain Res 673(2):313–319
Teune TM, van der Burg J, van der Moer J, Voogd J, Ruigrok TJ (2000) Topography of cerebellar nuclear projections to the brain stem in the rat. Prog Brain Res 124:141–172
Fredette BJ, Mugnaini E (1991) The GABAergic cerebello-olivary projection in the rat. Anat Embryol (Berl) 184(3):225–243
Medina JF, Nores WL, Mauk MD (2002) Inhibition of climbing fibres is a signal for the extinction of conditioned eyelid responses. Nature 416(6878):330–333
Jahnsen H (1986) Electrophysiological characteristics of neurones in the guinea-pig deep cerebellar nuclei in vitro. J Physiol 372:129–147
Llinás R, Mühlethaler M (1988) Electrophysiology of guinea-pig cerebellar nuclear cells in the in vitro brain stem-cerebellar preparation. J Physiol 404:241–258
Mouginot D, Gähwiler BH (1995) Characterization of synaptic connections between cortex and deep nuclei of the rat cerebellum in vitro. Neuroscience 64(3):699–712
Aizenman CD, Linden DJ (1999) Regulation of the rebound depolarization and spontaneous firing patterns of deep nuclear neurons in slices of rat cerebellum. J Neurophysiol 82(4):1697–1709
Raman IM, Gustafson AE, Padgett DE (2000) Ionic currents and spontaneous firing in neurons isolated from the cerebellar nuclei. J Neurosci 20(24):9004–9016
Gauck V, Jaeger D (2000) The control of rate and timing of spikes in the deep cerebellar nuclei by inhibition. J Neurosci 20(8):3006–3016
Czubayko U, Sultan F, Thier P, Schwarz C (2001) Two types of neurons in the rat cerebellar nuclei as distinguished by membrane potentials and intracellular fillings. J Neurophysiol 85(5):2017–2029
Monaghan PL, Beitz AJ, Larson AA, Altschuler RA, Madl JE, Mullett MA (1986) Immunocytochemical localization of glutamate-, glutaminase- and aspartate aminotransferase-like immunoreactivity in the rat deep cerebellar nuclei. Brain Res 363(2):364–370
Chen S, Hillman DE (1993) Colocalization of neurotransmitters in the deep cerebellar nuclei. J Neurocytol 22(2):81–91
Teune TM, van der Burg J, de Zeeuw CI, Voogd J, Ruigrok TJ (1998) Single Purkinje cell can innervate multiple classes of projection neurons in the cerebellar nuclei of the rat: a light microscopic and ultrastructural triple-tracer study in the rat. J Comp Neurol 392(2):164–178
Uusisaari M, Obata K, Knöpfel T (2007) Morphological and electrophysiological properties of GABAergic and non-GABAergic cells in the deep cerebellar nuclei. J Neurophysiol 97(1):901–911
Bagnall MW, Zingg B, Sakatos A, Moghadam S, Zeilhofer HU, du Lac S (2009) Glycinergic projection neurons of the cerebellum. J Neurosci 29(32):10104–10110
Palkovits M, Mezey E, Hamori J, Szentagothai J (1977) Quantitative histological analysis of the cerebellar nuclei in the cat. I. Numerical data on cells and on synapses. Exp Brain Res 28(1–2):189–209
Häusser M, Clark BA (1997) Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration. Neuron 19(3):665–678
Raman IM, Bean BP (1997) Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons. J Neurosci 17(12):4517–4526
Nam SC, Hockberger PE (1997) Analysis of spontaneous electrical activity in cerebellar Purkinje cells acutely isolated from postnatal rats. J Neurobiol 33(1):18–32
Thach WT (1968) Discharge of Purkinje and cerebellar nuclear neurons during rapidly alternating arm movements in the monkey. J Neurophysiol 31(5):785–797
Latham A, Paul DH (1971) Spontaneous activity of cerebellar Purkinje cells and their responses to impulses in climbing fibres. J Physiol 213(1):135–156
Khaliq ZM, Raman IM (2005) Axonal propagation of simple and complex spikes in cerebellar Purkinje neurons. J Neurosci 25(2):454–463
Monsivais P, Clark BA, Roth A, Häusser M (2005) Determinants of action potential propagation in cerebellar Purkinje cell axons. J Neurosci 25(2):464–472
van Kan PL, Gibson AR, Houk JC (1993) Movement-related inputs to intermediate cerebellum of the monkey. J Neurophysiol 69(1):74–94
Armstrong DM, Edgley SA (1984) Discharges of nucleus interpositus neurones during locomotion in the cat. J Physiol 351:411–432
McDevitt CJ, Ebner TJ, Bloedel JR (1987) Relationships between simultaneously recorded Purkinje cells and nuclear neurons. Brain Res 425(1):1–13
Lu B, Su Y, Das S, Liu J, Xia J, Ren D (2007) The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. Cell 129(2):371–383
Cody FW, Moore RB, Richardson HC (1981) Patterns of activity evoked in cerebellar interpositus nuclear neurones by natural somatosensory stimuli in awake cats. J Physiol 317:1–20
Sánchez-Campusano R, Gruart A, Delgado-García JM (2007) The cerebellar interpositus nucleus and the dynamic control of learned motor responses. J Neurosci 27(25):6620–6632
Pugh JR, Raman IM (2006) Potentiation of mossy fiber EPSCs in the cerebellar nuclei by NMDA receptor activation followed by postinhibitory rebound current. Neuron 51(1):113–123
Audinat E, Gähwiler BH, Knöpfel T (1992) Excitatory synaptic potentials in neurons of the deep nuclei in olivo-cerebellar slice cultures. Neuroscience 49(4):903–911
Anchisi D, Scelfo B, Tempia F (2001) Postsynaptic currents in deep cerebellar nuclei. J Neurophysiol 85(1):323–331
Akazawa C, Shigemoto R, Bessho Y, Nakanishi S, Mizuno N (1994) Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats. J Comp Neurol 347(1):150–160
Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH (1994) Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12(3):529–540
Momiyama A, Feldmeyer D, Cull-Candy SG (1996) Identification of a native low-conductance NMDA channel with reduced sensitivity to Mg2+ in rat central neurones. J Physiol 494(Pt 2):479–492
Pugh JR, Raman IM (2008) Mechanisms of potentiation of mossy fiber EPSCs in the cerebellar nuclei by coincident synaptic excitation and inhibition. J Neurosci 28(42):10549–10560
Telgkamp P, Raman IM (2002) Depression of inhibitory synaptic transmission between Purkinje cells and neurons of the cerebellar nuclei. J Neurosci 22(19):8447–8457
Telgkamp P, Padgett DE, Ledoux V, Woolley CS, Raman IM (2004) Maintenance of high-frequency inhibitory transmission at Purkinje to cerebellar nuclear synapses by spillover from boutons with multiple release sites. Neuron 41:113–126
Pugh JR, Raman IM (2005) GABAA receptor kinetics in the cerebellar nuclei: evidence for detection of transmitter from distant release sites. Biophys J 88(3):1740–1754
Jahnsen H (1986) Extracellular activation and membrane conductances of neurones in the guinea-pig deep cerebellar nuclei in vitro. J Physiol 372:149–168
Afshari FS, Ptak K, Khaliq ZM, Grieco TM, Slater NT, McCrimmon DR, Raman IM (2004) Resurgent Na currents in four classes of neurons of the cerebellum. J Neurophysiol 92(5):2831–2843
Aman TK, Raman IM (2007) Subunit dependence of Na channel slow inactivation and open channel block in cerebellar neurons. Biophys J 92(6):1938–1951
Zheng N, Raman IM (2009) Ca currents activated by spontaneous firing and synaptic disinhibition in neurons of the cerebellar nuclei. J Neurosci 29(31):9826–9838
Molineux ML, McRory JE, McKay BE, Hamid J, Mehaffey WH, Rehak R, Snutch TP, Zamponi GW, Turner RW (2006) Specific T-type calcium channel isoforms are associated with distinct burst phenotypes in deep cerebellar nuclear neurons. Proc Natl Acad Sci USA 103(14):5555–5560
Muri R, Knöpfel T (1994) Activity induced elevations of intracellular calcium concentration in neurons of the deep cerebellar nuclei. J Neurophysiol 71(1):420–428
Gauck V, Thomann M, Jaeger D, Borst A (2001) Spatial distribution of low- and high-voltage-activated calcium currents in neurons of the deep cerebellar nuclei. J Neurosci 21(15):RC158
Molineux ML, Mehaffey WH, Tadayonnejad R, Anderson D, Tennent AF, Turner RW (2008) Ionic factors governing rebound burst phenotype in rat deep cerebellar neurons. J Neurophysiol 100(5):2684–2701
Alviña K, Walter JT, Kohn A, Ellis-Davies G, Khodakhah K (2008) Questioning the role of rebound firing in the cerebellum. Nat Neurosci 11(11):1256–1258
Tadayonnejad R, Mehaffey WH, Anderson D, Turner RW (2009) Reliability of triggering postinhibitory rebound bursts in deep cerebellar neurons. Channels (Austin) 3(3):149–155
Morishita W, Sastry BR (1993) Long-term depression of IPSPs in rat deep cerebellar nuclei. Neuroreport 4(6):719–722
Aizenman CD, Manis PB, Linden DJ (1998) Polarity of long-term synaptic gain change is related to postsynaptic spike firing at a cerebellar inhibitory synapse. Neuron 21(4):827–835
Alviña K, Ellis-Davies G, Khodakhah K (2009) T-type calcium channels mediate rebound firing in intact deep cerebellar neurons. Neuroscience 158(2):635–641
Morishita W, Sastry BR (1995) Pharmacological characterization of pre- and postsynaptic GABAB receptors in the deep nuclei of rat cerebellar slices. Neuroscience 68(4):1127–1137
Ouardouz M, Sastry BR (2005) Activity-mediated shift in reversal potential of GABA-ergic synaptic currents in immature neurons. Brain Res Dev Brain Res 160(1):78–84
Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y (2009) GABA action in immature neocortical neurons directly depends on the availability of ketone bodies. J Neurochem 110:1330–1338
Morishita W (1996) Sastry BR Postsynaptic mechanisms underlying long-term depression of GABAergic transmission in neurons of the deep cerebellar nuclei. J Neurophysiol 76(1):59–68
Ouardouz M, Sastry BR (2000) Mechanisms underlying LTP of inhibitory synaptic transmission in the deep cerebellar nuclei. J Neurophysiol 84(3):1414–1421
Alviña K, Khodakhah K (2008) Selective regulation of spontaneous activity of neurons of the deep cerebellar nuclei by N-type calcium channels in juvenile rats. J Physiol 586(10):2523–2538
Linden DJ, Connor JA (1993) Cellular mechanisms of long-term depression in the cerebellum. Curr Opin Neurobiol 3(3):401–406
Miles FA (1981) Lisberger SG Plasticity in the vestibulo-ocular reflex: a new hypothesis. Annu Rev Neurosci 4:273–299
Medina JF, Mauk MD (1999) Simulations of cerebellar motor learning: computational analysis of plasticity at the mossy fiber to deep nucleus synapse. J Neurosci 19(16):7140–7151
Pugh JR, Raman IM (2009) Nothing can be coincidence: synaptic inhibition and plasticity in the cerebellar nuclei. Trends Neurosci 32(3):170–177
Zhang W, Linden DJ (2006) Long-term depression at the mossy fiber-deep cerebellar nucleus synapse. J Neurosci 26(26):6935–6944
Nelson AB, Krispel CM, Sekirnjak C, Du Lac S (2003) Long-lasting increases in intrinsic excitability triggered by inhibition. Neuron 40(3):609–620
Nelson AB, Gittis AH, du Lac S (2005) Decreases in CaMKII activity trigger persistent potentiation of intrinsic excitability in spontaneously firing vestibular nucleus neurons. Neuron 46(4):623–631
McCormick DA, Thompson RF (1984) Cerebellum: essential involvement in the classically conditioned eyelid response. Science 223(4633):296–299
Medina JF, Nores WL, Ohyama T, Mauk MD (2000) Mechanisms of cerebellar learning suggested by eyelid conditioning. Curr Opin Neurobiol 10(6):717–724
Hesslow G, Svensson P, Ivarsson M (1999) Learned movements elicited by direct stimulation of cerebellar mossy fiber afferents. Neuron 24(1):179–185
Jirenhed DA, Bengtsson F, Hesslow G (2007) Acquisition, extinction, and reacquisition of a cerebellar cortical memory trace. J Neurosci 27(10):2493–2502
Aizenman CD, Linden DJ (2000) Rapid, synaptically driven increases in the intrinsic excitability of cerebellar deep nuclear neurons. Nat Neurosci 3(2):109–111
Zhang W, Shin JH, Linden DJ (2004) Persistent changes in the intrinsic excitability of rat deep cerebellar nuclear neurones induced by EPSP or IPSP bursts. J Physiol 561(Pt 3):703–719
Caddy KW, Biscoe TJ (1979) Structural and quantitative studies on the normal C3H and Lurcher mutant mouse. Philos Trans R Soc Lond B Biol Sci 287(1020):167–201
Wetts R, Herrup K (1982) Interaction of granule. Purkinje and inferior olivary neurons in lurcher chimaeric mice. I. Qualitative studies. J Embryol Exp Morphol 68:87–98
Zuo J, De Jager PL, Takahashi KA, Jiang W, Linden DJ, Heintz N (1997) Neurodegeneration in Lurcher mice caused by mutation in δ2 glutamate receptor gene. Nature 388(6644):769–773
Sultan F, König T, Möck M, Thier P (2002) Quantitative organization of neurotransmitters in the deep cerebellar nuclei of the Lurcher mutant. J Comp Neurol 452(4):311–323
Linnemann C, Sultan F, Pedroarena CM, Schwarz C, Thier P (2004) Lurcher mice exhibit potentiation of GABA(A)-receptor-mediated conductance in cerebellar nuclei neurons in close temporal relationship to Purkinje cell death. J Neurophysiol 91(2):1102–1107
Garin N, Hornung JP, Escher G (2002) Distribution of postsynaptic GABA(A) receptor aggregates in the deep cerebellar nuclei of normal and mutant mice. J Comp Neurol 447(3):210–217
LeDoux MS, Lorden JF, Ervin JM (1993) Cerebellectomy eliminates the motor syndrome of the genetically dystonic rat. Exp Neurol 120(2):302–310
LeDoux MS, Lorden JF (2002) Abnormal spontaneous and harmaline-stimulated Purkinje cell activity in the awake genetically dystonic rat. Exp Brain Res 145(4):457–467
Beales M, Lorden JF, Walz E, Oltmans GA (1990) Quantitative autoradiography reveals selective changes in cerebellar GABA receptors of the rat mutant dystonic. J Neurosci 10(6):1874–1885
LeDoux MS, Hurst DC, Lorden JF (1998) Single-unit activity of cerebellar nuclear cells in the awake genetically dystonic rat. Neuroscience 86(2):533–545
Walter JT, Alviña K, Womack MD, Chevez C, Khodakhah K (2006) Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci 9(3):389–397
Acknowledgments
We would like to acknowledge all the members of the laboratory whose research is reviewed in this article: Fatemeh Afshari, Teresa Aman, Amy Gustafson, Zayd Khaliq, Dan Padgett, Jason Pugh, and Petra Telgkamp. We are especially grateful to Jason Bant and Teresa Aman for their contributions to Figures. Supported by NIH NS39395 (IMR).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zheng, N., Raman, I.M. Synaptic Inhibition, Excitation, and Plasticity in Neurons of the Cerebellar Nuclei. Cerebellum 9, 56–66 (2010). https://doi.org/10.1007/s12311-009-0140-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12311-009-0140-6