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Cells Aug 2023Thorase belongs to the AAA+ ATPase family, which plays a critical role in maintaining cellular homeostasis. Our previous work reported that Thorase was highly expressed...
Thorase belongs to the AAA+ ATPase family, which plays a critical role in maintaining cellular homeostasis. Our previous work reported that Thorase was highly expressed in brain tissue, especially in the cerebellum. However, the roles of Thorase in the cerebellum have still not been characterized. In this study, we generated conditional knockout mice (cKO) with Thorase deletion in Purkinje cells. Thorase cKO mice exhibited cerebellar degenerative diseases-like behavior and significant impairment in motor coordination. Thorase deletion resulted in more Purkinje neuron apoptosis, leading to Purkinje cell loss in the cerebellum of Thorase cKO mice. We also found enhanced expression of the inflammatory protein ASC, IL-1β, IL-6 and TNF-α in the Thorase cKO cerebellum, which contributed to the pathogenesis of cerebellar degenerative disease. Our findings provide a better understanding of the role of Thorase in the cerebellum, which is a theoretical basis for Thorase as a therapeutic drug target for neurodegenerative diseases.
Topics: Animals; Mice; Purkinje Cells; Cerebellum; Brain; Causality; ATPases Associated with Diverse Cellular Activities; Mice, Knockout
PubMed: 37626842
DOI: 10.3390/cells12162032 -
Nature Communications Jul 2021Axonal plasticity allows neurons to control their output, which critically determines the flow of information in the brain. Axon diameter can be regulated by activity,...
Axonal plasticity allows neurons to control their output, which critically determines the flow of information in the brain. Axon diameter can be regulated by activity, yet how morphological changes in an axon impact its function remains poorly understood. Axonal swellings have been found on Purkinje cell axons in the cerebellum both in healthy development and in neurodegenerative diseases, and computational models predicts that axonal swellings impair axonal function. Here we report that in young Purkinje cells, axons with swellings propagated action potentials with higher fidelity than those without, and that axonal swellings form when axonal failures are high. Furthermore, we observed that healthy young adult mice with more axonal swellings learn better on cerebellar-related tasks than mice with fewer swellings. Our findings suggest that axonal swellings underlie a form of axonal plasticity that optimizes the fidelity of action potential propagation in axons, resulting in enhanced learning.
Topics: Action Potentials; Animals; Axons; Brain; Cerebellum; Female; Learning; Male; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Purkinje Cells
PubMed: 34226561
DOI: 10.1038/s41467-021-24390-4 -
The European Journal of Neuroscience Oct 2021Serine/threonine kinase 17b (STK17B, also known as DRAK2) is known to be a downstream effector of protein kinase C (PKC) in the immune system, in particular T...
Serine/threonine kinase 17b (STK17B, also known as DRAK2) is known to be a downstream effector of protein kinase C (PKC) in the immune system, in particular T lymphocytes. PKC activity also plays a critical role for dendritic development and synaptic maturation and plasticity in cerebellar Purkinje cells. We present evidence that STK17B is strongly expressed in mouse cerebellar Purkinje cells starting in the early postnatal period and remaining highly expressed throughout adult stages and that STK17B is a target of PKC phosphorylation in the cerebellum. STK17B overexpression potentiates the morphological changes of Purkinje cells seen after PKC activation, suggesting that it is a downstream effector of PKC. A phosphorylation mimetic STK17B variant induced a marked reduction of Purkinje cell dendritic tree size, whereas the inhibition of STK17B with the novel compound 16 (Cpd16) could partially rescue the morphological changes of the Purkinje cell dendritic tree after PKC activation. These findings show that STK17B signalling is an important downstream effector of PKC activation in Purkinje cells. Furthermore, STK17B was identified as a molecule being transcriptionally downregulated in mouse models of SCA1, SCA7, SCA14 and SCA41. The reduced expression of STK17B in these mouse models might protect Purkinje cell dendrites from the negative effects of overactivated PKC signalling. Our findings provide new insights in the role of STK17B for Purkinje cell dendritic development and the pathology of SCAs.
Topics: Animals; Apoptosis Regulatory Proteins; Cerebellum; Mice; Protein Kinase C; Protein Serine-Threonine Kinases; Purkinje Cells; Serine; Spinocerebellar Ataxias
PubMed: 34536317
DOI: 10.1111/ejn.15465 -
Proceedings of the National Academy of... Jan 2021Activity of sensory and motor cortices is essential for sensorimotor integration. In particular, coherence between these areas may indicate binding of critical functions...
Activity of sensory and motor cortices is essential for sensorimotor integration. In particular, coherence between these areas may indicate binding of critical functions like perception, motor planning, action, or sleep. Evidence is accumulating that cerebellar output modulates cortical activity and coherence, but how, when, and where it does so is unclear. We studied activity in and coherence between S1 and M1 cortices during whisker stimulation in the absence and presence of optogenetic Purkinje cell stimulation in crus 1 and 2 of awake mice, eliciting strong simple spike rate modulation. Without Purkinje cell stimulation, whisker stimulation triggers fast responses in S1 and M1 involving transient coherence in a broad spectrum. Simultaneous stimulation of Purkinje cells and whiskers affects amplitude and kinetics of sensory responses in S1 and M1 and alters the estimated S1-M1 coherence in theta and gamma bands, allowing bidirectional control dependent on behavioral context. These effects are absent when Purkinje cell activation is delayed by 20 ms. Focal stimulation of Purkinje cells revealed site specificity, with cells in medial crus 2 showing the most prominent and selective impact on estimated coherence, i.e., a strong suppression in the gamma but not the theta band. Granger causality analyses and computational modeling of the involved networks suggest that Purkinje cells control S1-M1 phase consistency predominantly via ventrolateral thalamus and M1. Our results indicate that activity of sensorimotor cortices can be dynamically and functionally modulated by specific cerebellar inputs, highlighting a widespread role of the cerebellum in coordinating sensorimotor behavior.
Topics: Animals; Cerebellar Cortex; Cerebellum; Female; Humans; Male; Mice; Mice, Transgenic; Motor Cortex; Optogenetics; Purkinje Cells; Sensorimotor Cortex; Somatosensory Cortex; Ventral Thalamic Nuclei; Vibrissae
PubMed: 33443203
DOI: 10.1073/pnas.2015292118 -
International Journal of Molecular... Oct 2022is generally known as a causative gene for a spontaneous autosomal recessive mouse mutation, Purkinje cell degeneration (). There is enough evidence that the cytosolic...
is generally known as a causative gene for a spontaneous autosomal recessive mouse mutation, Purkinje cell degeneration (). There is enough evidence that the cytosolic function of the zinc carboxypeptidase (CP) domain at the C-terminus of the Nna1 protein is associated with cell death. On the other hand, this molecule's two nuclear localization signals (NLSs) suggest some other functions exist. We generated exon 3-deficient mice ( KO), which encode a portion of the N-terminal NLS. Despite the frameshift occurring in these mice, there was an expression of the Nna1 protein lacking the N-terminal side. Surprisingly, the phenotype did not occur in the KO mouse. Behavioral analysis revealed that they were less anxious when assessed by the elevated plus maze and the light/dark box tests compared to the control. Furthermore, they showed impairments in context-dependent and sound stimulus-dependent learning. Biochemical analysis of KO mice revealed a reduced level of the AMPA-type glutamine receptor GluA2 in the hippocampal synaptosomal fraction. In addition, the motor protein kinesin-1, which transports GluA2 to dendrites, was also decreased. These results indicate that is also involved in emotion and memory learning, presumably through the trafficking and expression of synaptic signaling molecules, besides a known role in cell survival.
Topics: Mice; Animals; Purkinje Cells; Serine-Type D-Ala-D-Ala Carboxypeptidase; Cell Survival; GTP-Binding Proteins; Nerve Degeneration; Emotions
PubMed: 36361749
DOI: 10.3390/ijms232112961 -
PloS One 2016Climbing fibres and parallel fibres compete for dendritic space on Purkinje cells in the cerebellum. Normally, climbing fibres populate the proximal dendrites, where...
Climbing fibres and parallel fibres compete for dendritic space on Purkinje cells in the cerebellum. Normally, climbing fibres populate the proximal dendrites, where they suppress the multiple small spines typical of parallel fibres, leading to their replacement by the few large spines that contact climbing fibres. Previous work has shown that ephrins acting via EphA4 are a signal for this change in spine type and density. We have used an in vitro culture model in which to investigate the ephrin effect on Purkinje cell dendritic spines and the role of integrins in these changes. We found that integrins α3, α5 and β4 are present in many of the dendritic spines of cultured Purkinje cells. pFAK, the main downstream signalling molecule from integrins, has a similar distribution, although the intenstity of pFAK staining and the percentage of pFAK+ spines was consistently higher in the proximal dendrites. Activating integrins with Mg2+ led to an increase in the intensity of pFAK staining and an increase in the proportion of pFAK+ spines in both the proximal and distal dendrites, but no change in spine length, density or morphology. Blocking integrin binding with an RGD-containing peptide led to a reduction in spine length, with more stubby spines on both proximal and distal dendrites. Treatment of the cultures with ephrinA3-Fc chimera suppressed dendritic spines specifically on the proximal dendrites and there was also a decrease of pFAK in spines on this domain. This effect was blocked by simultaneous activation of integrins with Mn2+. We conclude that Eph/ephrin signaling regulates proximal dendritic spines in Purkinje cells by inactivating integrin downstream signalling.
Topics: Animals; Cells, Cultured; Dendritic Spines; Embryo, Mammalian; Ephrins; Female; Focal Adhesion Kinase 1; Integrins; Nerve Fibers; Purkinje Cells; Rats; Rats, Sprague-Dawley; Synapses
PubMed: 27518800
DOI: 10.1371/journal.pone.0158558 -
Brain and Behavior Mar 2015An essential complement to molecular-genetic approaches for analyzing the function of the oculomotor circuitry in mice is an understanding of sensory and motor signal...
INTRODUCTION
An essential complement to molecular-genetic approaches for analyzing the function of the oculomotor circuitry in mice is an understanding of sensory and motor signal processing in the circuit. Although there has been extensive analysis of the signals carried by neurons in the oculomotor circuits of species, such as monkeys, rabbits and goldfish, relatively little in vivo physiology has been done in the oculomotor circuitry of mice. We analyzed the contribution of vestibular and nonvestibular signals to the responses of individual Purkinje cells in the cerebellar flocculus of mice.
METHODS
We recorded Purkinje cells in the cerebellar flocculus of C57BL/6 mice during eye movement responses to vestibular and visual stimulation.
RESULTS
As in other species, most individual Purkinje cells in mice carried both vestibular and nonvestibular signals, and the most common response across cells was an increase in firing in response to ipsiversive eye movement or ipsiversive head movement. When both the head and eyes were moving, the Purkinje cell responses were approximated as a linear summation of head and eye velocity inputs. Unlike other species, floccular Purkinje cells in mice were considerably more sensitive to eye velocity than head velocity.
CONCLUSIONS
The signal content of Purkinje cells in the cerebellar flocculus of mice was qualitatively similar to that in other species. However, the eye velocity sensitivity was higher than in other species, which may reflect a tuning to the smaller range of eye velocities in mice.
Topics: Action Potentials; Animals; Electrophysiological Phenomena; Eye Movements; Head Movements; Mice; Mice, Inbred C57BL; Oculomotor Nerve; Photic Stimulation; Physical Stimulation; Purkinje Cells; Reflex, Vestibulo-Ocular
PubMed: 25642393
DOI: 10.1002/brb3.310 -
PLoS Biology Sep 2021Purkinje cell (PC) discharge, the only output of cerebellar cortex, involves 2 types of action potentials, high-frequency simple spikes (SSs) and low-frequency complex...
Purkinje cell (PC) discharge, the only output of cerebellar cortex, involves 2 types of action potentials, high-frequency simple spikes (SSs) and low-frequency complex spikes (CSs). While there is consensus that SSs convey information needed to optimize movement kinematics, the function of CSs, determined by the PC's climbing fiber input, remains controversial. While initially thought to be specialized in reporting information on motor error for the subsequent amendment of behavior, CSs seem to contribute to other aspects of motor behavior as well. When faced with the bewildering diversity of findings and views unraveled by highly specific tasks, one may wonder if there is just one true function with all the other attributions wrong? Or is the diversity of findings a reflection of distinct pools of PCs, each processing specific streams of information conveyed by climbing fibers? With these questions in mind, we recorded CSs from the monkey oculomotor vermis deploying a repetitive saccade task that entailed sizable motor errors as well as small amplitude saccades, correcting them. We demonstrate that, in addition to carrying error-related information, CSs carry information on the metrics of both primary and small corrective saccades in a time-specific manner, with changes in CS firing probability coupled with changes in CS duration. Furthermore, we also found CS activity that seemed to predict the upcoming events. Hence PCs receive a multiplexed climbing fiber input that merges complementary streams of information on the behavior, separable by the recipient PC because they are staggered in time.
Topics: Action Potentials; Animals; Macaca mulatta; Male; Movement; Purkinje Cells; Saccades
PubMed: 34529650
DOI: 10.1371/journal.pbio.3001400 -
PLoS Computational Biology Mar 2019Cerebellar Purkinje cells mediate accurate eye movement coordination. However, it remains unclear how oculomotor adaptation depends on the interplay between the...
Cerebellar Purkinje cells mediate accurate eye movement coordination. However, it remains unclear how oculomotor adaptation depends on the interplay between the characteristic Purkinje cell response patterns, namely tonic, bursting, and spike pauses. Here, a spiking cerebellar model assesses the role of Purkinje cell firing patterns in vestibular ocular reflex (VOR) adaptation. The model captures the cerebellar microcircuit properties and it incorporates spike-based synaptic plasticity at multiple cerebellar sites. A detailed Purkinje cell model reproduces the three spike-firing patterns that are shown to regulate the cerebellar output. Our results suggest that pauses following Purkinje complex spikes (bursts) encode transient disinhibition of target medial vestibular nuclei, critically gating the vestibular signals conveyed by mossy fibres. This gating mechanism accounts for early and coarse VOR acquisition, prior to the late reflex consolidation. In addition, properly timed and sized Purkinje cell bursts allow the ratio between long-term depression and potentiation (LTD/LTP) to be finely shaped at mossy fibre-medial vestibular nuclei synapses, which optimises VOR consolidation. Tonic Purkinje cell firing maintains the consolidated VOR through time. Importantly, pauses are crucial to facilitate VOR phase-reversal learning, by reshaping previously learnt synaptic weight distributions. Altogether, these results predict that Purkinje spike burst-pause dynamics are instrumental to VOR learning and reversal adaptation.
Topics: Action Potentials; Adaptation, Physiological; Animals; Eye Movements; Humans; Learning; Long-Term Potentiation; Purkinje Cells; Reflex, Vestibulo-Ocular; Synapses
PubMed: 30860991
DOI: 10.1371/journal.pcbi.1006298 -
Neuron May 2019In this issue of Neuron, Du et al. (2019) demonstrate that the bicistronic CACNA1A gene encodes a transcription factor α1ACT, mutations in which are associated with...
In this issue of Neuron, Du et al. (2019) demonstrate that the bicistronic CACNA1A gene encodes a transcription factor α1ACT, mutations in which are associated with SCA6, that controls expression of genes important for cerebellar Purkinje cell development and excitability. Reduction of α1ACT in the adult is well tolerated, suggesting a potential new therapy for SCA6.
Topics: Adult; Calcium Channels; Cerebellum; Gene Expression Regulation; Humans; Infant, Newborn; Purkinje Cells; Spinocerebellar Ataxias
PubMed: 31121118
DOI: 10.1016/j.neuron.2019.04.041