Impact of parallel fiber to Purkinje cell long-term depression is unmasked in absence of inhibitory input

Boele, Henk−Jan; Peter, Saša; Brinke, Michiel M. ten; Verdonschot, Lucas; Ijpelaar, Anna C.H.G.; Rizopoulos, Dimitris; Gao, Zhenyu; Koekkoek, S.K.E.; Zeeuw, Chris I. De

doi:10.1126/sciadv.aas9426

Cited by 60 publications

(92 citation statements)

References 35 publications

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“…The latter 127 option is the most suitable one because translocated mGluR 7 receptors at the synapse 128 can open GIRK ion channels, which will drop the membrane potential and thus prevent 129 opening of Voltage-gated Ca +2 ion channels. Activation of GIRK ion channels causing a 130 drop in tonic firing rate during training has been observed in experiments [35,36]. long duration conditional response as observed in the experiment [12].…”

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confidence: 57%

“…As discussed above, stimulating separate sets of 614 parallel fibers can in principle initiate different conditional responses. While this can be 615 achieved by electrodes [12], it is challenging less so in terms of potential experimental 616 protocols for conditional training [35] but rather due to difficulties in selecting specific 617 fibers. An alternative could be to stimulate granule cells in the Granule layer of the 618 Cerebellum [76] since parallel fibers are axonal branches of the granule cells.…”

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A biochemical mechanism for time-encoding memory formation within individual synapses of Purkinje cells

Mandwal

Orlandi

Simon

et al. 2019

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Within the classical eye-blink conditioning, Purkinje cells within the cerebellum are known to suppress their tonic firing rates for a well defined time period in response to the conditional stimulus after training. The temporal profile of the drop in tonic firing rate, i.e., the onset and the duration, depend upon the time interval between the onsets of the training conditional and unconditional stimulus. Direct stimulation of parallel fibers and climbing fiber by electrodes was found to be sufficient to reproduce the same characteristic drop in the firing rate of the Purkinje cell. In addition, the specific metabotropic glutamate-based receptor type 7 (mGluR 7 ), which resides on the Purkinje cell synapses, was found responsible for the initiation of the response, suggesting an intrinsic mechanism within the Purkinje cell for the temporal learning. In an attempt to look for a mechanism for time-encoding memory formation within individual Purkinje cells, we propose a biochemical mechanism based on recent experimental findings. The proposed model tries to answer key aspects of the "Coding problem" of Neuroscience by focussing on the Purkinje cell's ability to encode time intervals through training. According to the proposed mechanism, the time memory is encoded within the dynamics of a set of proteins -mGluR 7 , G-protein, G-protein coupled Inward Rectifier Potassium ion channel, Protein Kinase A and Protein Phosphatase 1 -which self-organize themselves into a protein complex. The intrinsic dynamics of these protein complexes can differ and thus can encode different time durations. Based on their amount and their collective dynamics within individual synapses, the Purkinje cell is able to suppress its own tonic firing rate for a specific time interval. The time memory is encoded within the effective rate constants of the biochemical reactions and altering these rates constants means storing a different time memory. The proposed mechanism is verified by a simplified mathematical model and corresponding dynamical simulations of the involved biomolecules, yielding testable experimental predictions. Author summaryHebbian plasticity is a widely accepted form of learning that can encode memories in our brain. Spike-timing dependent plasticity resulting in Long-term Potentiation or Depression of synapses has become the default mechanistic explanation behind memory Introduction 1 How do we store memories in our brain? How do we retrieve and edit them when 2 required? Recent experimental findings have shed some light onto these fundamental 3 questions. Experiments have shown that memories are held within specific neuronal 4 populations [1-3]. Such populations, referred as memory engram cells [4, 5] store 5 memory either by forming or eliminating synapses [6, 7] or by altering synaptic 6 strengths between neurons [8, 9] within the population. These forms of learning and 7 memory formation fall under the widely accepted Hebbian learning paradigm [10]. 8 However, the individual contribution of each synapse to the engrams, an...

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A biochemical mechanism for time-encoding memory formation within individual synapses of Purkinje cells

Mandwal

Orlandi

Simon

et al. 2019

Preprint

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“…This also holds for relatively simple forms of cerebellum-dependent motor learning, such as delay eyeblink conditioning (EBC) [14,15] and adaptation of the vestibulo-ocular reflex (VOR) [16][17][18]. An important step forward has been the realization that we need to abandon attempts to link even simple behaviors to one specific type of cellular plasticity and instead appreciate learning as a result of multiple distributed, yet synergistic, plasticity events [19][20][21][22]. The question that we want to address here is whether cell-autonomous changes in membrane excitability are indeed a component of such plasticity networks and whether this intrinsic component is essential for the proper execution of a behavioral memory task.…”

Section: Introductionmentioning

confidence: 99%

SK2 channels in cerebellar Purkinje cells contribute to excitability modulation in motor-learning–specific memory traces

et al. 2020

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Neurons store information by changing synaptic input weights. In addition, they can adjust their membrane excitability to alter spike output. Here, we demonstrate a role of such "intrinsic plasticity" in behavioral learning in a mouse model that allows us to detect specific consequences of absent excitability modulation. Mice with a Purkinje-cell-specific knockout (KO) of the calcium-activated K + channel SK2 (L7-SK2) show intact vestibulo-ocular reflex (VOR) gain adaptation but impaired eyeblink conditioning (EBC), which relies on the ability to establish associations between stimuli, with the eyelid closure itself depending on a transient suppression of spike firing. In these mice, the intrinsic plasticity of Purkinje cells is prevented without affecting long-term depression or potentiation at their parallel fiber (PF) input. In contrast to the typical spike pattern of EBC-supporting zebrin-negative Purkinje cells, L7-SK2 neurons show reduced background spiking but enhanced excitability. Thus, SK2 plasticity and excitability modulation are essential for specific forms of motor learning.

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“…For all procedures on eyeblink conditioning we refer to the study done previously 63 . L7-TRPC3 KO mice, aged 16-25 weeks, were anesthetized with an isoflurane/oxygen mixture and surgically placed a so-called pedestal on the skull.…”

Section: Methodsmentioning

confidence: 99%

“…Inter-group comparisons were done by two-tailed Student's t test. For combined analysis of multiple sections, ANOVA for repeated measures was used to analyze eye-movement recording data; linear mixed-effect model analysis 63 (established in R version 1.1.442) was used to analyze eyeblink conditioning data. For a complete dataset, see Supplementary Table 2-6 .…”

Section: Methodsmentioning

confidence: 99%

TRPC3 is essential for functional heterogeneity of cerebellar Purkinje cells

et al. 2018

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23Despite the canonical homogenous character of its organization, the cerebellum plays 24 differential computational roles in distinct types of sensorimotor behaviors. However, the 25 molecular and cell physiological underpinnings are unclear. Here we determined the 26 contribution of transient receptor potential cation channel type C3 (TRPC3) to signal 27 processing in different cerebellar modules. Using gain-of-function and loss-of-function mouse 28 models, we found that TRPC3 controls the simple spike activity of zebrin-negative (Z-), but 29 not of zebrin-positive (Z+), Purkinje cells. Moreover, in vivo TRPC3 also regulated complex 30 spike firing and its interaction with simple spikes exclusively in Z-Purkinje cells. Finally, we 31 found that eyeblink conditioning, related to Z-modules, but not compensatory eye movement 32 adaptation, linked to Z+ modules, was affected in TRPC3 loss-of-function mice. Together, our 33 results indicate that TRPC3 is essential for the cellular heterogeneity that introduces distinct 34 physiological properties in an otherwise homogeneous population of Purkinje cells, conjuring 35 functional heterogeneity in cerebellar sensorimotor integration. 36 37Recently, it has been uncovered that the sole output neurons of the cerebellar cortex, the 47 Purkinje cells (PCs), can be divided into two main groups with a distinct firing behavior 10,11 . 48 One group, consisting of PCs that are positive for the glycolytic enzyme aldolase C, also 49 referred to as zebrin II 12,13 , shows relatively low simple spike firing rates, whereas the PCs in 50 the other group that form zebrin-negative zones, fire at higher rates 10 . Zebrin II demarcates 51 olivocerebellar modules, anatomically defined operational units each consisting of a closed 52 loop between the inferior olive, parasagittal bands of the cerebellar cortex and the cerebellar 53 nuclei 14,15 . Given that different motor domains are controlled by specific olivocerebellar 54 modules 14,16 , the differential intrinsic firing frequencies may be tuned to the specific neuronal 55 demands downstream of the cerebellum 17 . Thus, dependent on the specific behavior 56 controlled by the module involved, the PCs engaged may show low or high intrinsic firing as 57 well as related plasticity rules to adjust these behaviors. 58Cellular heterogeneity can drive differentiation in the activity and plasticity of individual 59 cells that operate within a larger ensemble 18 . The molecular and cellular determinants of 60 differential electrophysiological processing in the cerebellar PC modules are just starting to be 61 identified 19,20 . For example, while the impact of zebrin II itself is still unclear 10 , excitatory 62 amino acid transporter 4 (EAAT4) and GLAST/EAAT1 can directly modulate simple spike 63 activity of PCs as well as plasticity of their parallel fiber inputs in a zone specific manner 21,22 . 64 4 Likewise, phospholipase C subtype β4 (PLCβ4) is required for climbing fiber elimination and 65 PF-PC LTD through mGluR1 activation by spi...

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Impact of parallel fiber to Purkinje cell long-term depression is unmasked in absence of inhibitory input

Abstract: Simultaneous impairment of Purkinje cell inhibitory input and parallel fiber LTD severely affects cerebellar learning.

Cited by 60 publications

References 35 publications

A biochemical mechanism for time-encoding memory formation within individual synapses of Purkinje cells

A biochemical mechanism for time-encoding memory formation within individual synapses of Purkinje cells

SK2 channels in cerebellar Purkinje cells contribute to excitability modulation in motor-learning–specific memory traces

TRPC3 is essential for functional heterogeneity of cerebellar Purkinje cells

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