Christian Hansel

Research Summary
Neural networks are able to store information and to learn by adapting the efficacy of synaptic communication between neurons in an activity-dependent way. ‘Synaptic memory’ formation can be bidirectional: synapses can undergo long-term potentiation (LTP) or long-term depression (LTD). These processes participate in behavioral learning in specific ways that depend on the layout of the neuronal circuit that is studied. In our laboratory, we examine forms of synaptic and non-synaptic plasticity in the cerebellum, a brain area that is involved in fine adaptation of movements, but is involved in cognitive functions as well. In Marr-Albus-Ito models of cerebellar function, LTD at parallel fiber (PF) synapses onto Purkinje cells, which provide the sole output of the cerebellar cortex, is seen as a cellular correlate of motor learning, and forms of associative learning in general. LTD is induced by co-activation of PF synapses with the climbing fiber (CF) input, and is postsynaptically induced and expressed. Next to LTD, we also study a postsynaptic form of LTP at PF synapses that is induced by isolated PF activation and might provide a reversal mechanism for LTD (formally, LTD might also provide a reversal mechanism for LTP). We have recently shown that bidirectional plasticity at PF synapses is governed by induction rules that operate inverse to their counterparts at hippocampal and neocortical synapses: 1) PF-LTD needs larger calcium transients for its induction than LTP, and 2) PF-LTD is kinase-dependent (PKC / aCaMKII), whereas PF-LTP is phosphatase-dependent. Moreover, we have shown that the direction of synaptic gain change (potentiation or depression) depends on whether the CF input was co-activated (LTD) or not (LTP). This control by a qualitatively different heterosynaptic input provides a unique plasticity motif in the brain. In addition to LTD and LTP, we also examine intrinsic plasticity in Purkinje cells. We have shown that the intrinsic excitability of Purkinje cells can be amplified by a downregulation of calcium-dependent SK2-type potassium channels, and that this form of plasticity complements LTD and LTP in information storage. In the lab, we use patch-clamp recording techniques (incl. patch-clamp recordings from Purkinje cell dendrites), as well as confocal calcium imaging to study the cellular and molecular mechanisms underlying learning and memory. These studies are complemented by the use of additional techniques such as immunohistochemistry and behavioral testing. More recently, we also study the effects of alcohol on cerebellar function and motor adaptation, and the role of deficits in cerebellar associative learning in autism spectrum disorder (ASD).
Keywords
Intrinsic Plasticity, Synaptic Plasticity, Purkinje cell, Cerebellum, Neocortex
Education
  • University of Zurich, Switzerland, Diploma Zoology
  • Max-Planck-Institute for Brain Research, Frankfurt, Germany, Ph.D. Neurobiology
  • Johns Hopkins University, Baltimore, Postdoc Neurobiology
Biosciences Graduate Program Association
Publications
  1. Simmons DH, Titley HK, Hansel C, Mason P. Behavioral Tests for Mouse Models of Autism: An Argument for the Inclusion of Cerebellum-Controlled Motor Behaviors. Neuroscience. 2020 May 15. View in: PubMed

  2. Titley HK, Watkins GV, Lin C, Weiss C, McCarthy M, Disterhoft JF, Hansel C. Intrinsic Excitability Increase in Cerebellar Purkinje Cells after Delay Eye-Blink Conditioning in Mice. J Neurosci. 2020 03 04; 40(10):2038-2046. View in: PubMed

  3. Gill DF, Hansel C. Muscarinic Modulation of SK2-Type K+ Channels Promotes Intrinsic Plasticity in L2/3 Pyramidal Neurons of the Mouse Primary Somatosensory Cortex. eNeuro. 2020 Mar/Apr; 7(2). View in: PubMed

  4. Grasselli G, Boele HJ, Titley HK, Bradford N, van Beers L, Jay L, Beekhof GC, Busch SE, De Zeeuw CI, Schonewille M, Hansel C. SK2 channels in cerebellar Purkinje cells contribute to excitability modulation in motor-learning-specific memory traces. PLoS Biol. 2020 01; 18(1):e3000596. View in: PubMed

  5. Titley HK, Kislin M, Simmons DH, Wang SS, Hansel C. Complex spike clusters and false-positive rejection in a cerebellar supervised learning rule. J Physiol. 2019 08; 597(16):4387-4406. View in: PubMed

  6. Du X, Wei C, Hejazi Pastor DP, Rao ER, Li Y, Grasselli G, Godfrey J, Palmenberg AC, Andrade J, Hansel C, Gomez CM. a1ACT Is Essential for Survival and Early Cerebellar Programming in a Critical Neonatal Window. Neuron. 2019 05 22; 102(4):770-785.e7. View in: PubMed

  7. Ohtsuki G, Hansel C. Synaptic Potential and Plasticity of an SK2 Channel Gate Regulate Spike Burst Activity in Cerebellar Purkinje Cells. iScience. 2018 Mar 23; 1:49-54. View in: PubMed

  8. Hansel C. Deregulation of synaptic plasticity in autism. Neurosci Lett. 2019 01 01; 688:58-61. View in: PubMed

  9. Titley HK, Brunel N, Hansel C. Toward a Neurocentric View of Learning. Neuron. 2017 Jul 05; 95(1):19-32. View in: PubMed

  10. Piochon C, Titley HK, Simmons DH, Grasselli G, Elgersma Y, Hansel C. Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal. Proc Natl Acad Sci U S A. 2016 11 15; 113(46):13221-13226. View in: PubMed

  11. Piochon C, Kano M, Hansel C. LTD-like molecular pathways in developmental synaptic pruning. Nat Neurosci. 2016 09 27; 19(10):1299-310. View in: PubMed

  12. Grasselli G, He Q, Wan V, Adelman JP, Ohtsuki G, Hansel C. Activity-Dependent Plasticity of Spike Pauses in Cerebellar Purkinje Cells. Cell Rep. 2016 Mar 22; 14(11):2546-53. View in: PubMed

  13. Kloth AD, Badura A, Li A, Cherskov A, Connolly SG, Giovannucci A, Bangash MA, Grasselli G, Peñagarikano O, Piochon C, Tsai PT, Geschwind DH, Hansel C, Sahin M, Takumi T, Worley PF, Wang SS. Cerebellar associative sensory learning defects in five mouse autism models. Elife. 2015 Jul 09; 4:e06085. View in: PubMed

  14. Shih EK, Sekerková G, Ohtsuki G, Aldinger KA, Chizhikov VV, Hansel C, Mugnaini E, Millen KJ. The Spontaneous Ataxic Mouse Mutant Tippy is Characterized by a Novel Purkinje Cell Morphogenesis and Degeneration Phenotype. Cerebellum. 2015 Jun; 14(3):292-307. View in: PubMed

  15. Piochon C, Kloth AD, Grasselli G, Titley HK, Nakayama H, Hashimoto K, Wan V, Simmons DH, Eissa T, Nakatani J, Cherskov A, Miyazaki T, Watanabe M, Takumi T, Kano M, Wang SS, Hansel C. Corrigendum: Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nat Commun. 2015 Jan 27; 6:6014. View in: PubMed

  16. Titley HK, Hansel C. Asymmetries in Cerebellar Plasticity and Motor Learning. Cerebellum. 2016 Apr; 15(2):87-92. View in: PubMed

  17. Piochon C, Kloth AD, Grasselli G, Titley HK, Nakayama H, Hashimoto K, Wan V, Simmons DH, Eissa T, Nakatani J, Cherskov A, Miyazaki T, Watanabe M, Takumi T, Kano M, Wang SS, Hansel C. Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nat Commun. 2014 Nov 24; 5:5586. View in: PubMed

  18. van Beugen BJ, Qiao X, Simmons DH, De Zeeuw CI, Hansel C. Enhanced AMPA receptor function promotes cerebellar long-term depression rather than potentiation. Learn Mem. 2014 Dec; 21(12):662-7. View in: PubMed

  19. Grasselli G, Hansel C. Cerebellar long-term potentiation: cellular mechanisms and role in learning. Int Rev Neurobiol. 2014; 117:39-51. View in: PubMed

  20. Du X, Wang J, Zhu H, Rinaldo L, Lamar KM, Palmenberg AC, Hansel C, Gomez CM. Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6. Cell. 2013 Jul 03; 154(1):118-33. View in: PubMed

  21. Rinaldo L, Hansel C. Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber-Purkinje cell synapses via cannabinoid signaling. Proc Natl Acad Sci U S A. 2013 Jul 02; 110(27):11181-6. View in: PubMed

  22. Piochon C, Kruskal P, Maclean J, Hansel C. Non-Hebbian spike-timing-dependent plasticity in cerebellar circuits. Front Neural Circuits. 2012; 6:124. View in: PubMed

  23. He Q, Titley H, Grasselli G, Piochon C, Hansel C. Ethanol affects NMDA receptor signaling at climbing fiber-Purkinje cell synapses in mice and impairs cerebellar LTD. J Neurophysiol. 2013 Mar; 109(5):1333-42. View in: PubMed

  24. Ohtsuki G, Piochon C, Adelman JP, Hansel C. SK2 channel modulation contributes to compartment-specific dendritic plasticity in cerebellar Purkinje cells. Neuron. 2012 Jul 12; 75(1):108-20. View in: PubMed

  25. Buttermore ED, Piochon C, Wallace ML, Philpot BD, Hansel C, Bhat MA. Pinceau organization in the cerebellum requires distinct functions of neurofascin in Purkinje and basket neurons during postnatal development. J Neurosci. 2012 Apr 04; 32(14):4724-42. View in: PubMed

  26. Hosy E, Piochon C, Teuling E, Rinaldo L, Hansel C. SK2 channel expression and function in cerebellar Purkinje cells. J Physiol. 2011 Jul 15; 589(Pt 14):3433-40. View in: PubMed

  27. Rinaldo L, Hansel C. Ataxias and cerebellar dysfunction: involvement of synaptic plasticity deficits? Funct Neurol. 2010 Jul-Sep; 25(3):135-9. View in: PubMed

  28. Piochon C, Levenes C, Ohtsuki G, Hansel C. Purkinje cell NMDA receptors assume a key role in synaptic gain control in the mature cerebellum. J Neurosci. 2010 Nov 10; 30(45):15330-5. View in: PubMed

  29. Belmeguenai A, Hosy E, Bengtsson F, Pedroarena CM, Piochon C, Teuling E, He Q, Ohtsuki G, De Jeu MT, Elgersma Y, De Zeeuw CI, Jörntell H, Hansel C. Intrinsic plasticity complements long-term potentiation in parallel fiber input gain control in cerebellar Purkinje cells. J Neurosci. 2010 Oct 13; 30(41):13630-43. View in: PubMed

  30. Ohtsuki G, Piochon C, Hansel C. Climbing fiber signaling and cerebellar gain control. Front Cell Neurosci. 2009; 3:4. View in: PubMed

  31. van Woerden GM, Hoebeek FE, Gao Z, Nagaraja RY, Hoogenraad CC, Kushner SA, Hansel C, De Zeeuw CI, Elgersma Y. betaCaMKII controls the direction of plasticity at parallel fiber-Purkinje cell synapses. Nat Neurosci. 2009 Jul; 12(7):823-5. View in: PubMed

  32. Hansel C. Reading the clock: how Purkinje cells decode the phase of olivary oscillations. Neuron. 2009 May 14; 62(3):308-9. View in: PubMed

  33. Belmeguenai A, Botta P, Weber JT, Carta M, De Ruiter M, De Zeeuw CI, Valenzuela CF, Hansel C. Alcohol impairs long-term depression at the cerebellar parallel fiber-Purkinje cell synapse. J Neurophysiol. 2008 Dec; 100(6):3167-74. View in: PubMed

  34. Han VZ, Zhang Y, Bell CC, Hansel C. Synaptic plasticity and calcium signaling in Purkinje cells of the central cerebellar lobes of mormyrid fish. J Neurosci. 2007 Dec 05; 27(49):13499-512. View in: PubMed

  35. Yuan Q, Qiu DL, Weber JT, Hansel C, Knöpfel T. Climbing fiber-triggered metabotropic slow potentials enhance dendritic calcium transients and simple spike firing in cerebellar Purkinje cells. Mol Cell Neurosci. 2007 Aug; 35(4):596-603. View in: PubMed

  36. Jörntell H, Hansel C. Synaptic memories upside down: bidirectional plasticity at cerebellar parallel fiber-Purkinje cell synapses. Neuron. 2006 Oct 19; 52(2):227-38. View in: PubMed

  37. Hansel C, de Jeu M, Belmeguenai A, Houtman SH, Buitendijk GH, Andreev D, De Zeeuw CI, Elgersma Y. alphaCaMKII Is essential for cerebellar LTD and motor learning. Neuron. 2006 Sep 21; 51(6):835-43. View in: PubMed

  38. van Beugen BJ, Nagaraja RY, Hansel C. Climbing fiber-evoked endocannabinoid signaling heterosynaptically suppresses presynaptic cerebellar long-term potentiation. J Neurosci. 2006 Aug 09; 26(32):8289-94. View in: PubMed

  39. de Ruiter MM, De Zeeuw CI, Hansel C. Voltage-gated sodium channels in cerebellar Purkinje cells of mormyrid fish. J Neurophysiol. 2006 Jul; 96(1):378-90. View in: PubMed

  40. Hansel C. When the B-team runs plasticity: GluR2 receptor trafficking in cerebellar long-term potentiation. Proc Natl Acad Sci U S A. 2005 Dec 20; 102(51):18245-6. View in: PubMed

  41. Belmeguenai A, Hansel C. A role for protein phosphatases 1, 2A, and 2B in cerebellar long-term potentiation. J Neurosci. 2005 Nov 16; 25(46):10768-72. View in: PubMed

  42. Schmolesky MT, De Zeeuw CI, Hansel C. Climbing fiber synaptic plasticity and modifications in Purkinje cell excitability. Prog Brain Res. 2005; 148:81-94. View in: PubMed

  43. Coesmans M, Weber JT, De Zeeuw CI, Hansel C. Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control. Neuron. 2004 Nov 18; 44(4):691-700. View in: PubMed

  44. Weber JT, De Zeeuw CI, Linden DJ, Hansel C. Long-term depression of climbing fiber-evoked calcium transients in Purkinje cell dendrites. Proc Natl Acad Sci U S A. 2003 Mar 04; 100(5):2878-83. View in: PubMed

  45. Schmolesky MT, Weber JT, De Zeeuw CI, Hansel C. The making of a complex spike: ionic composition and plasticity. Ann N Y Acad Sci. 2002 Dec; 978:359-90. View in: PubMed

  46. Shen Y, Hansel C, Linden DJ. Glutamate release during LTD at cerebellar climbing fiber-Purkinje cell synapses. Nat Neurosci. 2002 Aug; 5(8):725-6. View in: PubMed