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).
University of Zurich
Switzerland
Diploma - Zoology
Max-Planck-Institute for Brain Research
Frankfurt, Germany
Ph.D. - Neurobiology
Johns Hopkins University
Baltimore
Postdoc - Neurobiology
Contiguity in perception: origins in cellular associative computations.
Contiguity in perception: origins in cellular associative computations. Trends Neurosci. 2024 03; 47(3):170-180.
PMID: 38310022
Intrinsic and synaptic determinants of receptive field plasticity in Purkinje cells of the mouse cerebellum.
Intrinsic and synaptic determinants of receptive field plasticity in Purkinje cells of the mouse cerebellum. bioRxiv. 2023 Aug 19.
PMID: 37502848
Climbing fiber multi-innervation of mouse Purkinje dendrites with arborization common to human.
Climbing fiber multi-innervation of mouse Purkinje dendrites with arborization common to human. Science. 2023 07 28; 381(6656):420-427.
PMID: 37499000
Overexpression of the autism candidate gene Cyfip1 pathologically enhances olivo-cerebellar signaling in mice.
Overexpression of the autism candidate gene Cyfip1 pathologically enhances olivo-cerebellar signaling in mice. Front Cell Neurosci. 2023; 17:1219270.
PMID: 37545882
Upregulation of SYNGAP1 expression in mice and human neurons by redirecting alternative splicing.
Upregulation of SYNGAP1 expression in mice and human neurons by redirecting alternative splicing. Neuron. 2023 05 17; 111(10):1637-1650.e5.
PMID: 36917980
Intrinsic threshold plasticity: cholinergic activation and role in the neuronal recognition of incomplete input patterns.
Intrinsic threshold plasticity: cholinergic activation and role in the neuronal recognition of incomplete input patterns. J Physiol. 2023 08; 601(15):3221-3239.
PMID: 35879872
The calcium sensor, rather than the route of calcium entry, defines cerebellar plasticity pathways.
The calcium sensor, rather than the route of calcium entry, defines cerebellar plasticity pathways. Proc Natl Acad Sci U S A. 2022 02 22; 119(8).
PMID: 35193964
Sensory Over-responsivity and Aberrant Plasticity in Cerebellar Cortex in a Mouse Model of Syndromic Autism.
Sensory Over-responsivity and Aberrant Plasticity in Cerebellar Cortex in a Mouse Model of Syndromic Autism. Biol Psychiatry Glob Open Sci. 2022 Oct; 2(4):450-459.
PMID: 36324646
Part II. J. C. Eccles, R. Llinas and K. Sasaki, The Excitatory Synaptic Action of Climbing Fibres on the Purkinje Cells of the Cerebellum, J Physiol, 182: 268-296, 1966: the Rise of the Complex Spike.
Part II. J. C. Eccles, R. Llinas and K. Sasaki, The Excitatory Synaptic Action of Climbing Fibres on the Purkinje Cells of the Cerebellum, J Physiol, 182: 268-296, 1966: the Rise of the Complex Spike. Cerebellum. 2021 06; 20(3):330-339.
PMID: 33638794
Why is synaptic plasticity not enough?
Why is synaptic plasticity not enough? Neurobiol Learn Mem. 2020 12; 176:107336.
PMID: 33137462