scholarly journals Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jui-Yi Hsieh ◽  
Brittany N Ulrich ◽  
Fadi A Issa ◽  
Meng-chin A Lin ◽  
Brandon Brown ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
High Frequency ◽  
Cerebellar Degeneration ◽  
Cerebellar Development ◽  
Adult Onset ◽  
Tonic Firing ◽  
Cell Excitability ◽  
Dendritic Branching

Mutations in KCNC3, which encodes the Kv3.3 K+ channel, cause spinocerebellar ataxia 13 (SCA13). SCA13 exists in distinct forms with onset in infancy or adulthood. Using zebrafish, we tested the hypothesis that infant- and adult-onset mutations differentially affect the excitability and viability of Purkinje cells in vivo during cerebellar development. An infant-onset mutation dramatically and transiently increased Purkinje cell excitability, stunted process extension, impaired dendritic branching and synaptogenesis, and caused rapid cell death during cerebellar development. Reducing excitability increased early Purkinje cell survival. In contrast, an adult-onset mutation did not significantly alter basal tonic firing in Purkinje cells, but reduced excitability during evoked high frequency spiking. Purkinje cells expressing the adult-onset mutation matured normally and did not degenerate during cerebellar development. Our results suggest that differential changes in the excitability of cerebellar neurons contribute to the distinct ages of onset and timing of cerebellar degeneration in infant- and adult-onset SCA13.

Encoding properties of the wing hinge stretch receptor in the hawkmothManduca sexta

2001 ◽  
Vol 204 (21) ◽  
pp. 3693-3702 ◽  
Author(s):  
Mark A. Frye
Keyword(s):  
Manduca Sexta ◽  
Instantaneous Frequency ◽  
High Frequency ◽  
Dynamic Deformation ◽  
Stretch Receptor ◽  
Tonic Firing ◽  
Frequency Burst ◽  
Natural Dynamic ◽  
Oscillation Rate

SUMMARYTo characterize the in vivo responses of the wing hinge stretch receptor of Manduca sexta, I recorded its activity and simultaneously tracked the up-and-down motion of the wing while the hawkmoth flew tethered in a wind tunnel. The stretch receptor fires a high-frequency burst of spikes near each dorsal stroke reversal. The onset of the burst is tightly tuned to a set-point in wing elevation, and the number of spikes contained within the burst encodes the maximal degree of wing elevation during the stroke. In an effort to characterize its mechanical encoding properties, I constructed an actuator that delivered deformations to the wing hinge and simultaneously recorded the resultant stretch and tension and the activity of the stretch receptor. Stimuli included stepwise changes in length as well as more natural dynamic deformation that was measured in vivo. Step changes in length reveal that the stretch receptor encodes the static amplitude of stretch with both phasic and tonic firing dynamics. In vivo sinusoidal deformation revealed (i) that the timing of stretch receptor activity is tightly phase-locked within the oscillation cycle, (ii) that the number of spikes per burst is inversely related to oscillation frequency and (iii) that the instantaneous frequency of the burst increases with oscillation rate. At all oscillation rates tested, the instantaneous frequency of the burst increases with amplitude.

scholarly journals Preterm Birth Impedes Structural and Functional Development of Cerebellar Purkinje Cells in the Developing Baboon Cerebellum

2020 ◽  
Vol 10 (12) ◽  
pp. 897
Author(s):  
Tara Barron ◽  
Jun Hee Kim
Keyword(s):  
Preterm Birth ◽  
Action Potential ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Late Gestation ◽  
Cerebellar Development ◽  
Layer Width ◽  
Action Potential Waveform ◽  
Developmental Features ◽  
Potential Waveform

Human cerebellar development occurs late in gestation and is hindered by preterm birth. The fetal development of Purkinje cells, the primary output cells of the cerebellar cortex, is crucial for the structure and function of the cerebellum. However, morphological and electrophysiological features in Purkinje cells at different gestational ages, and the effects of neonatal intensive care unit (NICU) experience on cerebellar development are unexplored. Utilizing the non-human primate baboon cerebellum, we investigated Purkinje cell development during the last trimester of pregnancy and the effect of NICU experience following premature birth on developmental features of Purkinje cells. Immunostaining and whole-cell patch clamp recordings of Purkinje cells in the baboon cerebellum at different gestational ages revealed that molecular layer width, driven by Purkinje dendrite extension, drastically increased and refinement of action potential waveform properties occurred throughout the last trimester of pregnancy. Preterm birth followed by NICU experience for 2 weeks impeded development of Purkinje cells, including action potential waveform properties, synaptic input, and dendrite extension compared with age-matched controls. In addition, these alterations impact Purkinje cell output, reducing the spontaneous firing frequency in deep cerebellar nucleus (DCN) neurons. Taken together, the primate cerebellum undergoes developmental refinements during late gestation, and NICU experience following extreme preterm birth influences morphological and physiological features in the cerebellum that can lead to functional deficits.

Spatial distribution of excitatory and inhibitory synapses on a Purkinje cell in a rat cerebellar culture

1993 ◽  
Vol 70 (4) ◽  
pp. 1316-1325 ◽  
Author(s):  
T. Hirano ◽  
K. Kasono
Keyword(s):  
Spatial Distribution ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Spatial Organization ◽  
Lucifer Yellow ◽  
Inhibitory Synapses ◽  
Presynaptic Neuron ◽  
Presynaptic Terminals ◽  
Excitatory And Inhibitory Synapses

1. The spatial distribution of excitatory and inhibitory synapses on cultured Purkinje cells was studied with fluorescence, scanning electron microscopy (SEM), and electrophysiological techniques. 2. Presynaptic terminals were identified with immunohistochemical staining of synaptophysin and the results were correlated with SEM micrographs. 3. Excitatory and inhibitory inputs onto the Purkinje cell were identified from the direction and pharmacology of the postsynaptic current. 4. The localization of the presynaptic terminals on the Purkinje cell was observed after electrophysiological identification by filling the presynaptic neuron with Lucifer yellow and the Purkinje cell with Texas red. 5. The axon and presynaptic terminals of excitatory and inhibitory inputs had a different spatial organization. Excitatory inputs from granule cells were exclusively localized on the dendrites of Purkinje cells, whereas inhibitory contacts were found on both the soma and dendrites. This result is similar to that described in vivo.

scholarly journals Maturation of Purkinje cell firing properties relies on neurogenesis of excitatory neurons

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Meike E van der Heijden ◽  
Elizabeth P Lackey ◽  
Ross Perez ◽  
Fatma S Ișleyen ◽  
Amanda M Brown ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Time Window ◽  
Mouse Development ◽  
Cerebellar Neurons ◽  
Cell Functions ◽  
Excitatory Neurons ◽  
Cell Firing ◽  
Firing Properties

Preterm infants that suffer cerebellar insults often develop motor disorders and cognitive difficulty. Excitatory granule cells, the most numerous neuron type in the brain, are especially vulnerable and likely instigate disease by impairing the function of their targets, the Purkinje cells. Here, we use regional genetic manipulations and in vivo electrophysiology to test whether excitatory neurons establish the firing properties of Purkinje cells during postnatal mouse development. We generated mutant mice that lack the majority of excitatory cerebellar neurons and tracked the structural and functional consequences on Purkinje cells. We reveal that Purkinje cells fail to acquire their typical morphology and connectivity, and that the concomitant transformation of Purkinje cell firing activity does not occur either. We also show that our mutant pups have impaired motor behaviors and vocal skills. These data argue that excitatory cerebellar neurons define the maturation time-window for postnatal Purkinje cell functions and refine cerebellar-dependent behaviors.

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

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251172
Author(s):  
Ayush Mandwal ◽  
Javier G. Orlandi ◽  
Christoph Simon ◽  
Jörn Davidsen
Keyword(s):  
Purkinje Cell ◽  
Firing Rate ◽  
G Protein ◽  
Purkinje Cells ◽  
Memory Formation ◽  
Time Interval ◽  
Biochemical Mechanism ◽  
Conditional Response ◽  
Tonic Firing ◽  
Time Encoding

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 conditional and unconditional training stimuli. 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 (mGluR7) 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 mechanism tries to answer key aspects of the “Coding problem” of Neuroscience by focusing 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—mGluR7, G-protein, G-protein coupled Inward Rectifier Potassium ion channel, Protein Kinase A, Protein Phosphatase 1 and other associated biomolecules—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 dynamics of the biochemical reactions and altering these dynamics means storing a different time memory. The proposed mechanism is verified by both a minimal and a more comprehensive mathematical model of the conditional response behavior of the Purkinje cell and corresponding dynamical simulations of the involved biomolecules, yielding testable experimental predictions.

Dynamic Synchronization of Purkinje Cell Simple Spikes

2006 ◽  
Vol 96 (6) ◽  
pp. 3485-3491 ◽  
Author(s):  
Soon-Lim Shin ◽  
Erik De Schutter
Keyword(s):  
Purkinje Cell ◽  
Firing Rate ◽  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Cerebellar Nuclei ◽  
Temporal Coding ◽  
Sharp Peak ◽  
Deep Cerebellar Nuclei

Purkinje cells (PCs) integrate all computations performed in the cerebellar cortex to inhibit neurons in the deep cerebellar nuclei (DCN). Simple spikes recorded in vivo from pairs of PCs separated by <100 μm are known to be synchronized with a sharp peak riding on a broad peak, but the significance of this finding is unclear. We show that the sharp peak consists exclusively of simple spikes associated with pauses in firing. The broader, less precise peak was caused by firing-rate co-modulation of faster firing spikes. About 13% of all pauses were synchronized, and these pauses had a median duration of 20 ms. As in vitro studies have reported that synchronous pauses can reliably trigger spikes in DCN neurons, we suggest that the subgroup of spikes causing the sharp peak is important for precise temporal coding in the cerebellum.

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

2019 ◽  
Author(s):  
Ayush Mandwal ◽  
Javier G. Orlandi ◽  
Christoph Simon ◽  
Jörn Davidsen
Keyword(s):  
Purkinje Cell ◽  
Firing Rate ◽  
Purkinje Cells ◽  
Protein Interactions ◽  
Effective Rate ◽  
Memory Formation ◽  
Time Interval ◽  
Biochemical Mechanism ◽  
Tonic Firing ◽  
Time Encoding

AbstractWithin 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 (mGluR7), 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 — mGluR7, 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 formation within a neuronal population. However, recent experiments of conditional eyeblink response in Purkinje cells have challenged this point of view by showing that these mechanisms alone cannot account for time memory formation in the Purkinje cell. To explain the underlying mechanism behind this novel synaptic plasticity, we introduce a biochemical mechanism based on protein interactions occurring within a single synapse. These protein interactions and the associated effective rate constants are sufficient to encode time delays by auto-induced inhibition on a single excitatory synapse, suggesting that synapses are capable of storing more information than previously thought.

scholarly journals Author response: Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo

2020 ◽  
Author(s):  
Jui-Yi Hsieh ◽  
Brittany N Ulrich ◽  
Fadi A Issa ◽  
Meng-chin A Lin ◽  
Brandon Brown ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Author Response ◽  
Cell Excitability

scholarly journals Dendritic Excitability Microzones and Occluded Long-Term Depression After Classical Conditioning of the Rabbit's Nictitating Membrane Response

1997 ◽  
Vol 77 (1) ◽  
pp. 86-92 ◽  
Author(s):  
Bernard G. Schreurs ◽  
Daniel Tomsic ◽  
Pavel A. Gusev ◽  
Daniel L. Alkon
Keyword(s):  
Classical Conditioning ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Parallel Fiber ◽  
Long Term Depression ◽  
Nictitating Membrane Response ◽  
Fiber Stimulation ◽  
In Cells

Schreurs, Bernard G., Daniel Tomsic, Pavel A. Gusev, and Daniel L. Alkon. Dendritic excitability microzones and occluded long-term depression after classical conditioning of the rabbit's nictitating membrane response. J. Neurophysiol. 77: 86–92, 1997. We made intradendritic recordings in Purkinje cells ( n = 164) from parasaggital slices of cerebellar lobule HVI obtained from rabbits given paired presentations of tone and periorbital electrical stimulation (classical conditioning, n = 27) or explicitly unpaired presentations of tone and periorbital stimulation (control, n = 16). Purkinje cell dendritic membrane excitability, assessed by the current required to elicit local dendritic calcium spikes, increased significantly in slices from animals that received classical conditioning. In contrast, membrane potential, input resistance, and amplitude of somatic and dendritic spikes were not different in slices from animals given paired or explicitly unpaired stimulus presentations. The location of cells with low thresholds for local dendritic calcium spikes suggested that there are specific sites for learning-related changes within lobule HVI. These areas may correspond to learning “microzones” and are consistent with locations of learning-related in vivo changes in Purkinje cell activity. Application of 4-aminopyridine, an antagonist of the rapidly inactivating potassium current I A, reduced the threshold for dendritic spikes in slices from naive animals to levels found in slices from trained animals. In cells where thresholds for eliciting parallel fiber–stimulated Purkinje cell excitatory postsynaptic potentials (EPSPs) were measured, levels of parallel fiber stimulation required to elicit a 6-mV EPSP as well as a 4-mV EPSP ( n = 30) and a Purkinje cell spike ( n = 56) were found to be significantly lower in slices from paired animals than unpaired controls. A classical conditioning procedure was simulated in slices of lobule HVI by pairing a brief, high-frequency train of parallel fiber stimulation (8 pulses, 100 Hz) with a brief, lower frequency train of climbing fiber stimulation (3 pulses, 20 Hz) to the same Purkinje cell. Following paired stimulation of the parallel and climbing fibers, Purkinje cell EPSPs underwent a long-term (>20 min) reduction in peak amplitude (−24%) in cells ( n = 12) from animals given unpaired stimulus presentations but to a far less extent (−9%) in cells ( n = 20) from animals given in vivo paired training. Whereas 92% of cells from unpaired animals showed pairing-specific depression, 50% of cells from paired animals showed no depression and in several cases showed potentiation. Our data establish that there are localized learning-specific changes in membrane and synaptic excitability of Purkinje cells in rabbit lobule HVI that can be detected in slices 24 h after classical conditioning. Long-term changes within Purkinje cells that effect this enhanced excitability may occlude pairing-specific long-term depression.

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